Journalist Richard Engel on Parenting a Child with Rett Syndrome

Episode Transcript

Dr. Correa:
From the American Academy of Neurology, I'm Dr. Daniel Correa.

Dr. Nath:
And I'm Dr. Audrey Nath.

Dr. Correa:
This is the Brain & Life podcast.

Dr. Nath:
Okay, Daniel, you may be familiar with the very familiar face on NBC: Richard Engel. He's the chief foreign correspondent who has reported from all over the world and won all sorts of awards for his reporting.
But we got to catch him with him about his son Henry and Henry's struggle with Rett syndrome and his care at Texas Children's Hospital. And I also got to catch up with Huda Zoghbi, the neurologist and researcher who discovered the gene for Rett syndrome.

Dr. Correa:
It's so important that we bring more attention and more of these rare conditions. We have a Rett Center at Albert Einstein College of Medicine where I work. It's just the opportunity to really help families learn more about these conditions and manage this. It's so important.

Dr. Nath:
Today, we are joined by Richard Engel, chief foreign correspondent for NBC News. He has written more than I could possibly list off right now, including his book And Then All Hell Broke Loose, published in 2016 about his two decade career in the Middle East and as a reporter. And he has won too many awards for his journalism to list, including multiple Peabody Awards.
Many of us have seen Richard Engel reporting from all around the world on our TVs. But today we are going to be talking about Richard's experience at home with a childhood neurological condition. His son, Henry, was diagnosed with Rett syndrome, a rare neurodevelopmental condition, and he passed away at the age of six years. Henry is absolutely remembered today amongst my former colleagues at Texas Children's Hospital. They studied his particular genetic mutation, and this research has advanced our knowledge of this disease and is contributing to active research into a cure for Rett syndrome.
Richard, welcome to the podcast. Thank you so much for sharing Henry's story.

Richard Engel:
Well, as you said, Henry's story is not over. Henry had a short life on this planet. He was born with this very difficult neurological disorder, which is extremely rare in boys.

Dr. Nath:
Yes, it is.

Richard Engel:
Quite rare in girls, but in boys it is... I don't want to say unheard of, but a few years ago it was almost unheard of. And now more and more cases are being discovered as the diagnostics are getting better and more people are getting tested.
But yes, he is still contributing. His cells are still being researched. And since his case was so unique, anything that is very unique is very rare. Very rare and unique are very valuable. That gives us a degree of comfort. It gives us hope. It gives us optimism that this horrible monster of a disease, which is so debilitating and takes so much, can one day be defeated or managed.

Dr. Nath:
Potentially. They are working on trials for potential medications, and that could be in the horizon for another family out there.
For anyone in our audience who may not be so familiar with child neurodevelopmental disorders or childhood epilepsies, we are speaking about Rett syndrome, which is a rare condition where there is regression in milestones. Typically, we may see a child that was able to roll or was able to speak and then have regression. And then seizures that may be very, very difficult to control. This is due to a gene mutation.
I want to hear from you. When did you guys start to notice that Henry was maybe having some trouble?

Richard Engel:
That was a brilliant outline. Obviously this is your field, so I'm not surprised you did it so well.
Rett syndrome in girls, which is by far the most common, what generally happens with girls is the girls are born and they look like there's nothing wrong with them. There's no particular issue in many cases. And then by the time they reach one and a half, two years old, bad things start to occur. They start to lose their skills. They start to have that regression. They start to rub their hands together. They generally lose the ability to speak, to walk if they'd been walking. And then all kinds of medical issues start ensuing.
With boys, since it's so rare, generally the condition in boys is not sustainable with life. The boys aren't born at all, so it's very, very rare because there's something has happened to allow them to be born and allow them to live on the planet.
Henry didn't have that same pattern with girls, which by the way, is so difficult for the children, but also so difficult for the parents because they're really blindsided. They see this girl. She's developing. She's walking. She's talking. She's got friends. She's going to school. Then suddenly it starts to wither away and the girls start to fall down, and they start to lose their ability to communicate.
With Henry, we knew right away that something was off while he was still in the hospital right after birth. Because he looked beautiful, he was great. His eyes were open, he was crying. And to be honest, when I say I should clarify. My wife noticed, Mary.
I didn't really notice at first. This was our first child. I didn't really know what that experience was like. I mean, how many adults, unless you grew up on it or you have it yourself, really spend that much time holding newborn babies for an-

Dr. Nath:
Many people don't.

Richard Engel:
... extended period of time or trying to feed them? You see somebody else's baby. You maybe hold them for a second, but you don't really engage that much.
But she could just sense holding him, holding him against her chest, holding him against her breast, that something was wrong. He wasn't suckling. He didn't really seem to have the strength. He was floppy...

Dr. Nath:
Low tone, yeah.

Richard Engel:
It's an ugly word, but everyone understands what it means. And now I know because we have a second child and when he was born, when Theo was born, our second child who's now three, I held him. I was like, "Oh, this is a very different experience." You could feel the muscles moving under his skin. There was rigidity there. If you held him up, he almost did Pilates. He did the plank position. He put his head up and he would put his arms out like he was Superman.
Henry wasn't like that. If you held him in the middle, his legs would dangle. And then there's a classic test that I didn't realize how important it is, but it is so fundamental. Where they take with a doctor, pediatrician or anybody do it, you take your child and you put them on their feet. They should resist. They should. When they touch the ground or a surface, they should push back against it. He wasn't doing that.
We knew there was something wrong with muscle tone, and we started testing right away. But he was making some milestones. He did roll over. He was eating. It was complicated because he wasn't breastfeeding, but we were using a bottle. That was complicated, and we had to use a dropper to push the formula more into his mouth so he wouldn't have to pull it out of any-

Dr. Nath:
So you don't have to use much mouth muscle. Yeah, yeah.

Richard Engel:
Yeah, so we knew something was wrong. But we certainly didn't know it was Rett, and we didn't know what it was at all.
They did all the tests and everything was working. His eyes were working. His he ears were working. He could see. He could hear. He could respond to light. They did blood tests. His organs all seemed to be in good shape. All the bases were there. It just wasn't coming together with this kind of energy.
After about a year, we were getting very concerned. Then eventually after numerous conversations, we had a genetic test done, a full genetic test, which back then was rare and complicated. The result took a very long time, and it was done through research laboratory-

Dr. Nath:
Was this whole exome sequencing by chance?

Richard Engel:
It was a whole exome sequence.

Dr. Nath:
Oh, that was more rare back then. Even now it can be difficult to obtain that sort of testing. Whole exome sequencing, for our audience, is basically sequencing the entire working part of the genome base pair by base pair by base pair.
This is very time-consuming even now, but certainly about 10 years ago that this would've been even harder to obtain.

Richard Engel:
We didn't pay for it because he was part of a... We submitted. We said he could be part of a research. Whatever material you find, you can use toward research. Just do this test, please. It still took several months to get any kind of results back.
But unfortunately the results were not good. They found something because they did his whole genetic scan. You get a blueprint for his whole DNA sequencing. When you look at the blueprint, when you look at his... It's not computer code. It's human code. There was a typo in his human code.
One of the sequences was abnormal, and it was in his gene called MECP2, or MECP2. I've never heard of it. Nobody's ever heard of it, unless you study this stuff. Who's ever heard of this?
Apparently, it is profoundly important, profoundly important. Because it helps regulate not just brain function, it helps regulate brain function to regulate every other kind of function. It was described to me as the conductor of an orchestra.
The instruments were all there. The brain was there. The eyes were there. The organs were there. Everything was intact. But there was this break in his genetic code that didn't allow any real coordination.

Dr. Nath:
That's a really good explanation of MECP2, by the way.
I want to hear from your perspective as a parent. I know you've had some time now to look back on this and work with the researchers and work with Texas Children's Hospital on this.
But at that moment when you found out that there was something very wrong, what was your reaction? Did you have it in your gut that you knew something was going to come up? Were you blindsided? Was it some of both?

Richard Engel:
I was slow to catch on initially. My wife, mother's instinct, intuition, just holding him she knew something was wrong.
I was the one who was more listening to the other people saying, "Oh no, he'll snap out of it. He'll grow out of it," because he didn't look sick. He looked so perfect and beautiful, and that's-

Dr. Nath:
[inaudible 00:11:39] smiles. Yeah, there are the pictures. Yeah.

Richard Engel:
I was wrong to think that. You should notice it.
I also travel a lot for work. Sometimes the work can be very, very, very busy. There's periods when a war comes along. I could be gone for months at a time.
That also changed how I saw things. Because I would come back and he hadn't changed. He hadn't developed. He wasn't doing anything different than when I left several months before. That perspective frightened me, especially when I would come back from a trip and then I saw him around other children. Mary was really the hands-on, day-to-day carer.
But I went to this playgroup and it was nice. Except I saw him and we were holding him, Henry, and we were playing with him on the floor. He did to have some movement. He could crawl, like an army crawl where you move with your hands. Suddenly, I'm looking around. These kids are throwing balls. They're pointing. They're jumping on things.
Mary and I, we have a real... This is serious problem here. There's something really, really... This is not delays anymore. He's in a different ballpark. Then we got the diagnosis, and the diagnosis confirmed that unfortunately, as science is now and as science was then, this was an irreversible condition.

Dr. Nath:
I'm really glad you're talking about this. Because even in my career as a pediatric neurologist, I have only ever seen girls with Rett. Actually, this is even helpful for me to know this, that like, oh, okay, it will present a bit differently in a boy perhaps. It can be more severe and start even earlier.

Richard Engel:
You're the genetic. You explain it. But as it was explained to me and as I process it, this gene was on the X chromosome. It was broken. Girls have another backup of the same gene, and that's why they start to develop. They start to walk. And then eventually these two systems, one that's broken, one that's healthy, clash and counter out each other. Rett syndrome manifest.
Since he only had one X and it was broken, there was no... There was only Y. There was no other X. But the reason he lived, the reason he was born and lived to six at all, is that his gene wasn't completely dead. It wasn't completely destroyed. It was producing a little bit of the protein. It was producing enough to keep him in the state that he was, but not enough to go further. Which is why he never had that period of development and then regression. The exact type of mutation he had in that particular place along the gene had never been documented before.
We cried a lot. I mean, I was in Korea. I was in South Korea. I was with the US military. They were delivering some missile defense systems because it was a time of increased tensions with the North Koreans. And actually because they were delivering these missile defense systems, it exasperated the tensions even more.
I was there on an assignment and it was in the middle of the night. I was in this convoy of military vehicles and these giant missile defense systems on flatbed trucks. They stopped every once in a while to just take rest breaks and refuel and look at the road. These convoys stopped periodically.
I used that opportunity because I had had an appointment to talk to this geneticist. Said, "Could you call me on such and such a date? I think we're going to have a result." I'm focusing on this story, but the only thing I've got on my mind is when I'm going to make this call, when I'm going to make this call.
We stopped, and I got in touch with the doctor. He was confused by the result because he hadn't come across boys that have this mutation. But I remember distinctly him telling me, "No, this is a serious neurological disorder. Your son is going to have a very different life than the one I had imagined." That was the moment then that the dreams that you had had, this idea that you still are hanging on to maybe this is just a phase he's going to step out of it, that was taken away at that moment.
I just remember getting back into the car was... It was tough. That was really hard. Finished the story and then went back home. Obviously I'd spoken to my wife before then, and then we learned more after I got home. Unfortunately, the information just didn't get better.

Dr. Nath:
That's unbelievable. You were in the middle of a convoy in Korea when you found out the full extent of this news.
I'd like to know. After getting back to home with your family, what sort of experience did you have reaching out to support groups such as with the Rett Foundation and other epilepsy foundations? What was your experience like with that and connecting with other families?

Richard Engel:
So Mary and I, and I wonder if this is common, we decided early on we're going to beat this thing. We're going to beat it. We're going to have smash it. I'm like, "I know people." Like you think, "Oh, I know people. I can fix this." If I had had lots of money, I'm going to buy my way out of it.
But I'm a journalist, I don't have lots of money. I have lots of contacts, right? I start blanketing the phones. I call everybody I know all across. And it's not that I have lots of science friends, but I'm calling friends who know friends who know friends. I spoke to the Mayo Clinic and hospitals in Switzerland. I spoke to hospitals in New York and pulled every string, every connection I had to find ways. I was like, "We're going to beat this."
Mary reached out to the community. If I was going, that was my approach, and she was reaching out in the community. So reaching out online, going into all the different chat rooms, trying to get all the grassroots information she could get, how to deal with it. Okay, it is what it is. We're going to have to... Henry's here and we want him to be happy and healthy and strong and engaged and loved as long as possible while we were going to beat this.
We set up in our minds we've got X number of years. We actually called it a five-year plan. We thought, "Okay, we've got five years. Let's do this. Let's do this, let's do this." I think we started out with a great deal of energy, enthusiasm. Optimism even, frenetic activity to try and connect with the best experts and the families who knew the most about this.
Then I also was like, "Okay, I have access to television." All right, let's use that platform. Let's raise awareness. Let's do everything we can. Also for the other parents, because the more we lived with this experience, the more we realized how difficult it is for us and for other parents out there. We just started engaging.
I don't want to say over time you lose that enthusiasm, but as several years go by, you start to realize maybe we're not going to beat this in five years. Maybe this is not going to work on our time schedule. Mary and I, we're a team working on this until the end. Right until end, we were a team.

Dr. Nath:
It's interesting that you say that. It's worth bringing up for any other families that are listening that having a child with special needs can be a very large stressor on families and on marriages.

Richard Engel:
It's expensive. It's emotionally devastating. You love your child so much, so you get over the... Okay, you mourn the future that you thought you were going to have. Okay, you got to get over that. Because that future, that ship, has sailed. Okay, I feel bad for myself. Okay, forget about that. That ship has sailed, too.
He's here. He's in this world, and he needs to have the best time possible. We focused on what can we do to keep him engaged, to keep him healthy, to keep him active. We never did or never even considered just putting him in a chair and turning on the TV and leaving him be. That never happened.

Dr. Nath:
To make the most of every day that he had.

Richard Engel:
And since he couldn't entertain himself, and a lot of kids like this can't entertain themselves, we had to be his entertainers. Mary sang. I did everything I could. We were always up in his face. Sounds like it was distracting, but cuddling him, kissing him, up in his face, embracing him, some TV. Whatever it could be to keep him engaged.
We worked with communication devices. Mary was using these flip books, and we were able to get some communication, which was hard to do. Mary was really dedicated, really patient about that, to try and get a yes or a no. Yes and nos, or if you can say yes or no or you can communicate yes or no, you can engage with the world a lot more than if you can't.
We learned to read his facial expressions. We learned to just to watch him and stay with him. And so yes, it is, going back to what you said, for couples, a lot of couples don't make it.

Dr. Nath:
Exactly, yeah.

Richard Engel:
The strain is so high. You're sleep deprived. You're stressed. Your anger... You're not necessarily angry with each other because neither of us did this. It's not his fault, it's not our fault. But there's anger and sadness, and that breaks up a lot of marriages.

Dr. Nath:
It's so common that we end up seeing this a lot in our clinics and hear about how these stresses are affecting families.
We try to encourage people to get therapy, get someone to talk to. But nothing takes away that anger and that stress and that sleep deprivation like that. There's truly nothing that can take it away.

Richard Engel:
You need help. Luckily, we had a lot of things going for us. I had a good job. Mary didn't have to work. I say that we didn't have to work. She busted her as working with him.

Dr. Nath:
Day and night, yeah.

Richard Engel:
Day and night, day and night, day and night. But she didn't have a outside paid job outside the house, so that allowed her to dedicate to Henry. We had good insurance. We have good friends. We had a strong relationship going into this. This didn't happen while we were in the throes of already some crisis. Our relationship was really strong, and then suddenly this happened. But that didn't have to be the case.
We had a lot of things going for us already. A lot of people don't have those. So if you don't have those, try and get them. Get the support from people. Get the support from family. Get the support from friends. You need the time. You need the breaks. We had people who were helping us who would take Henry for the night sometimes. One of his therapists said, "I'll take Henry for the night." Okay. We trusted her implicitly. She was wonderful. She was his physical therapist. She'd known him for years.
She did that a couple of times for us, and it allowed us to just have dinner, have a glass of wine, not have to be worried. Just toward the end, Henry had very serious respiratory issues, so he was on a BiPAP machine throughout the night, which had to be monitored. This was a 24-hour commitment. Just to have a night off, it was great. It was great. Not because we didn't want to be around Henry that night, but it just allowed us to make ourselves stronger for ourselves and for him.

Dr. Nath:
People don't talk about this enough.

Richard Engel:
If people make these and they're good offers, take them.

Dr. Nath:
Yes, yes. What it's like to be a caregiver in the moment, days and nights, for years. Yeah, absolutely. You need a little bit of help at times.
Before I let you go run off and interview other people and fly across the world, I want to know something else from you. As a parent that had a medically complex first child and then had a second child, who I'm assuming is healthy, how do you manage your own anxiety with the second kid?

Richard Engel:
We did a lot of testing ahead of time. We leaned heavily into science. There are certain families who rolled the dice on this. We didn't do that. I couldn't have done that. We were able to handle the strain. Not easily, there were rough times over these almost seven years.
But if we had had another child that had serious, complex need along these lines, I don't know if we would've gotten through. It would've been just too much. We leaned heavily. We did every possible test and beyond to make sure that he was healthy.

Dr. Nath:
Even intellectually knowing, okay, this second child does not have this MECP2 gene mutation, are you still kind of psychologically just scared, given what your first experience was like? Or have you come to terms with it with radical acceptance? That happened, and this is different.

Richard Engel:
I think it's the latter. That happened, and this is different.

Dr. Nath:
Okay.

Richard Engel:
You could tell from the moment I held him just this is different.
Now you obviously he's your child, and after having been through trauma, when I see him walk down the stairs, my heart goes up into my throat. Because I'm like, "Don't do this to me. Don't do this. We can't handle this."

Dr. Nath:
You know what we went through.

Richard Engel:
Yeah, you know what we went through. And as he's thrown himself onto things. Are you kidding me? I don't need this. So aside from that...

Dr. Nath:
That's relatable.

Richard Engel:
We're okay.

Dr. Nath:
Yeah.
Well, thank you for talking about this from that very, very personal parental perspective. There's so much literature we can read about, gene mutations and the ins and outs of the science, but to hear as a parent what that was like... I think for our listeners who may have medically complex children or children with epilepsy, genetic mutations that may be rare, it may be nice to hear your voice and know that, okay, I'm not alone in this.

Richard Engel:
That's why I started to do stories about the special needs community in general. One, because I wanted to help raise some money and awareness toward research, so there was a self-interest in there. I was like, "I want these researchers back in the lab working on genetic disorders." I want that now, and I want to put a little pressure on them any way I can through news reports.
But it was also to try and reach out to some of my new colleagues, these other parents, and to say, "You're not alone." It was really hard. It is harder than anyone possibly realizes. It's harder on every level.
It can be very lonely. That was something I hadn't anticipated going to the playground with a child who can't get out of a chair and play. The parents don't come up to you. Sometimes they do, but sometimes they don't. Oftentimes, they don't.
Other children stare. You walk down the street, and particularly as the special needs become more and more complex and acute and obvious... Later toward the end, he had an NG tube in his nose and he was trembling quite aggressively. It was an obvious thing when we were walking down the street.
It's very lonely. You feel like people aren't making eye contact with you. You're just walking there, and you're living in this reality. People are comfortable. They're afraid. I wanted to basically tell people you're not alone.
Yes, it is scary. Yes, it is terrible. But it is life, and life is tough and scary. However bad it is for us as the caregivers, we got to be there and show strength because these kids, they are totally dependent upon us.

Dr. Nath:
Well, thank you for shedding light on both the rare aspects of what Henry had, as well as the more common things that you guys went through as parents of special needs child with everyone.

Richard Engel:
And thank you. You're carrying this torch, too. You've dedicated your life to this science. I want you, and all of your colleagues, please beat this for all of us.

Dr. Nath:
Absolutely. Thank you.

Richard Engel:
All right, thank you.

Dr. Nath:
Is this episode leaving you wanting more? Get the latest tips on healthy living and management for more than 250 neurologic conditions by visiting brainandlife.org where you can learn about neurology every day powered by trusted neurologists.
Now, to learn more about Rett syndrome. This is a total treat. I will be speaking with Huda Zoghbi. She is the neurologist and scientist who discovered the gene that causes Rett syndrome.
She is currently a professor at the Baylor College of Medicine and the director of the Jan and Dan Duncan Neurological Research Institute, as well as an investigator at the Howard Hughes Medical Institute.
Hello, Dr. Zoghbi.

Dr. Zoghbi:
Hello, Dr. Nath. So very nice to see you.

Dr. Nath:
I want to start just in your own words. How is it that you got to studying Rett syndrome, and how did you start to figure out that there was a gene responsible for this?

Dr. Zoghbi:
I chose a career to be a pediatric neurologist. After finishing pediatrics, I was fascinated by the brain and decided I'm going to do pediatric neurology.
In our training at Texas Children's Hospital, we go and see patients in the clinics that come with various neurological disorders. I was in my first year of training in neurology, and I walk into the clinic. I see this young girl and hear her story and was really intrigued. She had Rett syndrome.
The way it went, she came to us because her parents, who are very observant and the father's a professor at Texas A&M, they noticed that she did very well for about two years of age. But after two, she stopped doing things she did well. She used to rhyme nursery rhymes. She used to use a few words, run and greet her dad at the door when he came from work.
And all of that stopped. Besides all her normal skills stopping, she acquired new symptoms. Instead of using her hands, she started constantly ringing her hands. And then her gait, which was very steady and stable, slowly became less stable. Then after that, she started holding her breath and sometimes breathing fast, sometimes holding her breath. Eventually, she did have seizures.
She came to us, because after three years of that regression, the parents have been seeking for answers and they came to see can we figure out what's wrong. That was my first encounter with Rett syndrome. And it happened that the month I saw her, a paper was published from Europe.

Dr. Nath:
Oh, that's serendipitous.

Dr. Zoghbi:
That's right, by Dr. Bengt Hagberg. He had a paper published describing cases from Europe that he has seen. He's called it autism and dementia ataxia, that's how he described it, disorder. Because they regress, so he called it dementia. They had features of social withdrawal, loss of language, stereotype behavior. That's why he called it autism. He saw that they were all girls. They were 35 girls.
As he started talking about it in Europe, somebody told him, "Well, you know what? In 1966, there was a pediatrician called Andreas Rett who described few cases." But it's written in German. No one has read it.

Dr. Nath:
Are you serious?

Dr. Zoghbi:
In honor of Professor Rett, he called the disorder Rett syndrome. It was the first time that the description of the disorder was now in the English language. It was actually published in a neurology journal, the Annals of Neurology. That paper came the same month.
My patient, Ashley's pediatrician, subscribes to journal services that bring her relevant papers on childhood disorders. Somebody gave her that particular paper. She referred us the patient and sent the paper. Could this be the disorder that she has?
When we saw the patient, I saw her as an intern and then discussed it with my attendings, Dr. Percy and Dr. Riccardi, and all of us agreed. She absolutely has Rett syndrome. I was really intrigued and kept thinking about her.
Because for when we think about childhood disorders, we think of them falling in a couple of categories. You're either born with a disease, and early on in infancy you will show symptoms. You'll be left with these symptoms for life. This is how most childhood intellectual disabilities and developmental disorders are.
Or you are born healthy and then sometimes after year, two years or longer, you would lose skills. That's because of some degeneration. These are typically neurodegenerative disorders.
But Rett was unique. And this was both in Ashley, who I saw, and in all the girls reported by Dr. Hagberg in that they were unique in that you're born healthy for a period of time. Then you lose skills, but then you can become an adult and no evidence of degeneration. That was intriguing. It wasn't any degenerative disorder, yet you're regressing and losing skills.
That was that one week in October when I met her. Then a week later I was in a different clinic where, as a neurology intern, you get to pick the case you want to see. I picked the diagnosis of cerebral palsy. The reason I picked cerebral palsy is because I knew that's a misdiagnosis. It's just something that people don't know the cause. There's motor problems, they're going to call it cerebral palsy, I think maybe I can figure something out.
I opened my office door for the patient to walk in. She was a 12-year-old, and she's walking and ringing her hands exactly like Ashley did the week before her. She also had all the same symptoms I saw in Ashley.

Dr. Nath:
What are the chances? One week apart. Nobody was talking about this yet.

Dr. Zoghbi:
That's right, so one week apart. And now you've got two girls that have exactly the same symptoms. They check all the criteria that were described as the criteria needed to diagnose Rett syndrome.
Just like your reaction, what are the chances so far for a disease that no one has reported on in the United States? No one has seen. I see two in one week. And that-

Dr. Nath:
Unbelievable.

Dr. Zoghbi:
... made me believe that there must be more cases. So I went to the clinic volunteers. The clinic where I saw this patient is called the Blue Bird Circle Clinic. It's run by volunteers, and they're really wonderful ladies who just-

Dr. Nath:
They are.

Dr. Zoghbi:
... seeing the patients and help the clinicians, help them navigate social services, and so on.
I asked, they were my electronic health record equivalent. I went to them and I said, "Look, if I gave you these keywords, female, developmental delay, balance problems, ataxia, and seizures, can you find me every chart that has these features in the girl?
They said they will. They came back a week later with 35 charts. I reviewed the charts, and I was able to find five cases with Rett syndrome clearly, from just reading the clinical description. I was able to find more.
We brought in all these girls, and we all worked together with my supervisors and attending. What we learned from studying their spinal fluid is that the metabolites of dopamine and serotonin were decreased. That told us that perhaps in their brain there's reduction of these neurotransmitters.
We published that paper in 1985 in the New England Journal of Medicine. Once you publish it, now all clinicians will recognize it. They'll start sending us the patients. Quickly became the largest clinic for Rett syndrome. And the Blue Bird Circle Clinic became the Blue Bird Circle Rett Center Clinic.
That what inspired me to think that this must be genetic. They were all females and they all had a similar clinical course. And for me, the fact they were all females told me it has to be genetics. Anything environmental should affect both males and females, right?

Dr. Nath:
That's right. Yeah, yeah, that makes sense.

Dr. Zoghbi:
The only confusing thing that made people doubt my hypothesis and that this is a genetic disease is that it was always one in a family. You never see again. And back in the '80s when we thought of a genetic disease, we thought of it either as inherited, where the parent is affected and they can pass the gene. So 50/50 chance of passing the gene.
Or, where each parent is a carrier and they each pass the gene. You see it in the child, but once in a blue moon, you're going to see it in another child. There one in four chance you'll see it in another child.
But Rett was not like either. It was always one in a family.

Dr. Nath:
No other cousins. No other siblings just-

Dr. Zoghbi:
Correct.

Dr. Nath:
Exactly. Yeah, that's unusual.

Dr. Zoghbi:
That's why people doubted this being a genetic disorder. How could it be a genetic disorder when it's just one? That was the big challenge.
The reason I was convinced this had to be genetic is two things. One, always a female. Why should it always affect female? There has to be something specific making it appear in females.
The biggest reason that convinced me there is a gene that causes Rett syndrome is the fact every girl went through the same course. They were healthy for a while, some of them six months, some a year, some two years. Then after that they slowly lost their skills. They all developed hand ringing, and they all developed the same symptoms.
To me, thinking about how the brain works, I figured there has to be a gene that's dictating that. When it's happening, the order with which the symptoms are coming. It's got to be that. And that's where I decided I'm going to now leave clinical medicine, go to the lab, learn how to do research.
This is a case where the patient inspired me to pursue the cause of their disease. That required this new skill of doing genetic research. That's why I went to the lab and I learned how to do gene cloning genetic studies. ,

Dr. Nath:
You went and learned all these skills to answer this question. That's just incredible to me.

Dr. Zoghbi:
And the DNA sequencing technology was not what it is today. You couldn't take the patient's DNA and sequence it. It had to be done systematically with some hypothesis. I had to eliminate part of the genome by thinking, since it's only girls, maybe it's on the X chromosome.

Dr. Nath:
Okay, okay. That narrows it down a little bit.

Dr. Zoghbi:
Right. I did a couple of experiments to give me hints. It's on the X chromosome because it's only females. The idea being because females have two x chromosomes. If one of them have the mutation, they will show the disease. But males who only have one X, if they have a mutation, they may not make it. They'll be so severe they don't have the other X to protect them.
I had a wonderful postdoc, her name was Ruthie Amir. She was tireless and she, like me, was passionate about finding this gene. She really went gene by gene on that portion of the X chromosome till one day she found a mutation. When she sequenced, she found it in five girls and called me.
I was in disbelief. I had just come from an overseas trip and she came with the notebooks to the house and we looked and it was real. We confirmed it, and then we were convinced. So I think that her resilience, I will always admire and appreciate.
That's what led me to focus on the X. Then on the X, you have to now figure out where. You start looking and looking and looking. Occasionally, once, one in a 100, we might see two relatives in a family. You think that maybe the mom passed it on, but she's not symptomatic.

Dr. Nath:
That's right, yeah.

Dr. Zoghbi:
Or she may have a mutation in her oocytes.

Dr. Nath:
Her egg cells, basically. Yeah.

Dr. Zoghbi:
Right. So that led us to narrow the region on the X to about 30 million base pairs and eventually to 10 million base pair.

Dr. Nath:
It's like a needle in a haystack.

Dr. Zoghbi:
Exactly. Which is in the context, it's like trying to find a person in the United States, no GPS, no map, and no address.
But then we narrowed it down to the southwest part of the United States. That's your X chromosome. We still haven't found them, but now we narrowed it down to perhaps the coastal cities of Houston and that of Texas. Now, we're trying to find it. And so it was really marching and knocking door by door. We would look at gene by gene. That's why it took us a long time because the technology wasn't there.
So in 1999, 16 years to the day from seeing my first Rett syndrome patient, we were able to find the gene.

Dr. Nath:
You spent 16 years.

Dr. Zoghbi:
From the day I saw her and thinking about her till we found it.
But I think what's really important, we learned that sporadic disease, which once in the family can still be genetic, can still be caused by a gene.

Dr. Nath:
Richard Engel was talking about how Henry's case was so unique because he is a boy who has an X and a Y chromosome instead of a girl with two X chromosomes.
Briefly, and partially just to keep Henry's memory alive, what did you learn from a case like Henry's?

Dr. Zoghbi:
As I mentioned, Rett is seen in girls because it's too severe to be. When it's imposed, they die typically by the first or second year of life. Because unlike the girls that they have a bunch of cells with the healthy X, in boys, all the cells have the X with a mutation.
What really was unique about Henry is he had a mutation, first of all that no one else has had. So it was a unique mutation.

Dr. Nath:
Oh, wow. Yeah.

Dr. Zoghbi:
You're not sure it's what's causing his diseases. And he had motor problem, he's had some regression, but from the beginning he had delay in motor abilities.
The first thing we wanted to know is is this mutation causing this disease? Is this the mutation that's causing this disease? Because we've never seen it before. We cannot be sure it's affecting the MECP2, the MECP2 protein.
The first thing we did, we took cells from Henry and we measured the protein. We found it to be reduced. That gave us a clue that it's doing something to the protein. But to be 100% sure it's doing something that's affecting all his motor function, we then put the mutation in a mouse and created a mouse model. The mice replicated all the features we've seen in Henry.
That told us of all of the genes that Henry carries, it's that one amino acid change in the MECP2 protein that's causing his symptoms.

Dr. Nath:
You've discovered this because of him.

Dr. Zoghbi:
That's right. So now that we know this what can we learn from it? We learn two things from it. We learn that the level of the protein is decreased, and we learned that it's binding to DNA is decease. Which gets me to tell you what does MECP2 do?
It binds DNA at a particular nucleic acid, cytosine. When it's methylated, this protein binds. When it binds, it pretty much affect the expression of many other genes. Think of it as the conductor of an orchestra. Think of the orchestra members as different genes in our brain, and think of this protein as the conductor telling these genes when to express, when make something too much or too little. You know you have to do the music. It has to be very much harmonious. They have to express at a particular time for it to be a harmony.
In the absence of this gene, you lose that. And the levels of many other genes in the brain are changing in many directions that's affecting brain function.

Dr. Nath:
That makes sense because the patients with Rett syndrome don't just have one particular issue. They can have several things that really invoke the whole brain, essentially. Seizures and motor issues and breathing issues. That really kind of makes sense, which you didn't know in the 1980s.
Based on everything you've learned over all of these decades of work, what is in the future in terms of potentially medications we could use for Rett syndrome?

Dr. Zoghbi:
Right. Basically getting back to Henry, what we really learned from Henry's studies is that there's reduction of the protein and reduction in its binding. We started looking at strategy where we can increase the protein and the idea if we increase the protein, could we make things better?
We are now finalizing stories that we're really showing that perhaps if we can increase Henry's protein, even though that it's not perfect, it can help. If that's the truth, we can then apply that. We can apply that to a variety of other mutations that cause Rett syndrome. Because we know 75% of Rett girls have a mutation where they make the protein but the protein is not quite normal. Either it doesn't bind as well, or its levels are slightly reduced.
If that's the case, and maybe if we can find ways to increase that protein, that could be helpful. That's one potential therapy to think about in the future. This is why we continue to work with Henry's cells. We continue to work with his mouse model because it's the ideal model for us to learn from and to focus on to really tweak things.

Dr. Nath:
Oh, wow. I think his parents would love to hear that.

Dr. Zoghbi:
Find ways to test, right? To test a new molecule or a new drug or a new strategy to increase the protein. That's what we're doing.

Dr. Nath:
Yeah. That is such a hopeful message for everyone listening who has a child that maybe has been diagnosed with Rett syndrome or many other genetic syndromes. Because you're right, there are lessons that we can learn from one model that could translate to either new treatments or even the way we do physical therapy with everyone else.
I just want to say thank you for your work, and thank you for spending 16 years finding that gene. Because that helps so many other people with Rett as well as other genetic disorders. And thank you for joining us.

Dr. Zoghbi:
Well, thank you.
I have to say before I close that I always say I'm grateful for the mentors, who taught me how to be a scientist but most importantly, I'm really grateful for the patients who have inspired me. Ashley and many other Rett girls have inspired me. Henry inspired me to think differently, and we're coming now with new strategies to increase the level of the MECP2 protein. I would not have thought to go in that direction before meeting Henry.
Most important, I'm one person, and Rett was coined in 1999. Lots of work has have been. That's really the wonderful trainees, students, fellows, technicians, all the people who do the hard work in my lab and other labs. They're the future, and they're the ones that give me hope work will continue until we have much better therapies.

Dr. Nath:
Absolutely. Thank you so much.

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Journalist Richard Engel on Parenting a Child with Rett Syndrome

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