Part One: Community Stories of Navigating a Rare Epilepsy Diagnosis

Episode Transcript

Dr. Daniel Correa:
From the American Academy of Neurology, I'm Dr. Daniel Correa. This is the Brain & Life podcast.
Now, our typical episodes, we interview an individual or person in the community living with a different neurologic condition. We help you learn about it and then we end up also talking with a medical expert on some key topics to understand better about that condition and about our overall brain health. And this episode and in our following episode, we're going to do a series of stories highlighting a rare condition that can cause both developmental delay, autistic features and seizures. The mutations to the gene that result in this condition were only identified as recently as 2009. And then in 2013 it became increasingly clear the role and the importance of the gene that affects cognitive development or development of our thinking, like we think of with kids playing with blocks and talking, and even in certain epilepsies.
In 2018, Mike Graglia and Ashley Evans' son, Tony, was diagnosed at age four with a mutation in SYNGAP1, after he started developing some of the symptoms that are seen in many other people living with mutations of the SYNGAP1 gene. Mike and Ashley couldn't find the resources they needed to answer their questions, and couldn't accept the fact that so little research was going on to understand the condition and then the idea of finding a possible cure and better treatments.
Mike left his work in tech and at a social justice organization to found the SynGAP Research Fund when their son Tony was diagnosed, with the goal of developing resources they needed, supporting other families, fundraising for new research and changing the course of this condition over a very short period. Since 2018, the SynGAP Research Fund, or SRF, has raised millions of dollars and accelerated our understanding of this condition, leading to development of potential treatments now in research studies. These are leaps in science that normally take decades. With the SRF, hope and support is moving forward quickly for this community.
We were inspired by this story that they've brought to the community in child neurology and in epilepsy and all the doctors that are out there working to help their patients, and so we partnered with the SRF to bring you the story of three unique families. Stay tuned in our discussion this week, we'll featured two families and with specialists out of Madrid, Spain. And then in the following week, we'll continue that discussion to wrap up these stories and our discussion to better understand this condition. Although it's a rare epilepsy, it's something that we can all learn from and really the inspiration of this foundation moving forward, our awareness, understanding, and research is a model I think everyone can take something from.
Today I'm overjoyed to be joined by Paulina Polanco. She's joining us from the Central Valley in California. She's a sister and full-time care partner for her twin sisters Libertad and Esparanza. Her and her family have been on a long journey with Libby and Espy, passed their birth complications, autism diagnosis, various special needs, seizures, and many years later, a diagnosis of a rare genetic epilepsy. She's joining us with other families in our series with stories about living with SYNGAP, a rare epilepsy in coordination with SRF. Thank you so much, Paulina, for joining us.

Paulina Polanco:
Thank you so much for having me and for that beautiful introduction.

Dr. Daniel Correa:
At age six, your family rejoice and welcomed your twin sisters. How did their introduction to the world go?

Paulina Polanco:
So they were born prematurely on September 15th, which I just learned is National Brain Health Day. So that day holds a lot of significance to us. And Espy had a heart condition and an ear condition when she was born, so at three months she had her first open heart surgery. And Libby was born healthy, thankfully. But yes, since birth we've kind of had to deal with a lot of health issues, a lot of going to the doctor. So it's been a rough ride since the very beginning.

Dr. Daniel Correa:
Yeah. Did Libby and Espy have seizures early in life, or what was it and when was it that the family and doctors noticed that there were issues aside from their birth complications?

Paulina Polanco:
So at three they were diagnosed with autism and intellectual disability. They never showed any signs of seizures or absence seizures or anything of that kind. So it was only until Espy had her first seizure at the end of 2021 that we knew pretty much that that was related to SynGAP1.

Dr. Daniel Correa:
So at age 17, after that many years and in the middle of the pandemic August 2020, Libby and Espy were both formally diagnosed with something called SYNGAP1. Where did this come from and what did you and your family know about SYNGAP1 or even any other genetic epilepsy at that time?

Paulina Polanco:
We didn't know anything about SYNGAP1. So the organization, Simons, reached out to my parents and they invited them to send some mouth samples from the twins and them. Through that the diagnosis came back for SYNGAP1, but at that time it didn't really mean anything to us. It was just another diagnosis to add to the list.
And then towards the end of 2021, December 29th I believe, that was when our lives changed. So I was in my room and I heard a loud plop coming from the other side of the house. And so I want to go see what it was, like maybe one of the twins dropped something. Or I just wanted to check on them. And then that's when I found Espy having her seizure.
It was really scary because that had never happened before to either of them. I had never even seen a seizure before. So honestly I didn't even know if I was going to see my sister anymore after that night. And so it was really hard. It was a really hard time. And we called an ambulance and my dad went to the hospital with her, and then an hour later he sent us a picture of her sitting up on her iPad acting like nothing had happened. So it was good to see her okay and being herself after such a traumatic experience.
And so I was under the impression that the seizure was caused by her falling off of the bed. I thought because it was late at night, she got sleepy and she fell and the impact caused the seizure. But a few days later coming out of doctor's appointment in the parking lot, she had another seizure, so that was our confirmation that it was something else. Because I was afraid that it was going to be like a brain tumor, until my dad remembered seeing under the SYNGAP1 symptoms that epilepsy was symptom of SYNGAP1. And so he made the connection between that.
But my mom did take it a little bit harder. She said that she felt like she was starting all over again and she was afraid. So it was really difficult to know that it was going to be a lifelong condition, but it was also a relief to know that it wasn't something fatal and that it was manageable because we had already been dealing with SYNGAP1 our entire lives with them.

Dr. Daniel Correa:
It's reassuring that it wasn't a symptom of something else and that it wasn't something you already weren't handling or taking care of. You guys had been there and caretakers and care partners for your sisters for years already. Most importantly though, once Espy was starting to take medications and seeing the doctors that could help treat her and her seizures, is she back to all the many of the things that she likes to do and the way that she interacts and communicates with you guys?

Paulina Polanco:
Once we got her on the right medication that works well for her, she is back to normal. You wouldn't even tell that she has seizures or has epilepsy. She loves to watch videos, she always giggles at the pictures and the songs that she listens to. She loves getting tickled. And so for me, I think I'm her favorite, honestly, because she doesn't request tickles or hugs from anybody else. And so she will ask me for tickles, she'll squeeze me and she's her normal self. So it's really reassuring to know that it's working for her. The medications that she's on are working for her.

Dr. Daniel Correa:
Has Libby had any challenges with seizures, or that really hasn't come up necessarily for her?

Paulina Polanco:
It hasn't come up for her. She had an ambulatory EEG done, so she had the nodes on her head and I think it was for a week and it was just tracking her brain activity. And I think it came back as inconclusive. I'm not sure if they found anything that was abnormal or concerning.

Dr. Daniel Correa:
So they didn't see any definite seizures during that time.

Paulina Polanco:
Yeah.

Dr. Daniel Correa:
And then I imagine the doctors probably had a discussion with your parents and your family as to whether or not to put her on medicine or to wait and see.

Paulina Polanco:
We're kind of just waiting and seeing if anything ever shows up, which hopefully nothing ever shows up.

Dr. Daniel Correa:
It just points out how different even one genetic cause can be from person to person. Tell us some about Libby. I mean we've heard some about Espy, how are their personalities alike and how are they different?

Paulina Polanco:
They're very different. You can even see it in the videos that we've taken of them on their birthday. We are all singing to them Happy Birthday and Libby's enjoying it and it looks like she's conducting the choir because she's so happy and flapping her hands. And then Espy's angry, she's over it. She wants to go to her room.

Dr. Daniel Correa:
So what have you learned from your sisters?

Paulina Polanco:
We've learned a lot. They teach us a lot about life. They teach us unconditional love. Their love, I think, transcends words. They show us how to love in different ways. They've taught us patience. They've taught us persistence, resilience. They've gone through so much in their lives and they've been able to overcome everything that life has thrown at them and act like nothing has happened.

Dr. Daniel Correa:
Sometimes people talk about caregiving as a burden. It's come up as in discussions we've had with several people. But in a way it sounds like they have made you and your family in part better persons.

Paulina Polanco:
Oh definitely. It's definitely exhausting, but they are kind of like our driving force, I think, in our family. They help us become more bonded.

Dr. Daniel Correa:
Building on what you've learned as a sibling of two sisters with autism and one with epilepsy, what would you share with others that have a loved one with these medical conditions?

Paulina Polanco:
At first we wanted them to be like other kids. We thought that they would like the same thing that other neurotypical kids would like, like Disneyland, going on trips with us. So we would take them with us to Mexico, to wherever we went. But then we soon found out that wasn't their interest. They didn't like that and it was very stressful on them and on us. So eventually we learned that it's important to let them be who they are. So I think it's important for families to accept their family member as they are, to take advantage of the situation even, to learn more about life, about themselves and about how to treat other people and to not give up because you're not alone and there are a lot of people who are going through the same thing that you might be.

Dr. Daniel Correa:
So much of what you said is important for all of us, just in a relationship with anyone. We can't make someone else fit our own expectations. And your voice and your perspective is important for all of us to hear. Thank you for sharing your light, both with your sisters and with the rest of us and our listeners.

Paulina Polanco:
Thank you so much for having me, giving me your time and for having this podcast as well, for not only creating awareness about SynGAP1 but about other neurological conditions and epilepsies. So thank you for your work.

Dr. Daniel Correa:
I am here with Dr. Marta Caceres Dahiya. She's a Colombian who completed her medical degree in Medellin, then worked with underserved communities in Columbia before coming to the US to pursue further medical training in internal medicine, and then became later a radiation oncologist in Texas and she now practices in Fort Worth. But today she joins us as the mother caregiver and friend of her daughter Sophia, supporting her journey living with intellectual disability, psychiatric outbursts and epilepsy complications of the SynGAP1 syndrome. She has also joined the board of the SRF in supporting their efforts towards research and community education. Thank you so much, Marta for joining us today.

Dr. Marta Caceres Dahiya:
Thank you so much for having me.

Dr. Daniel Correa:
Can we go back, maybe you can tell us about you and your family and life in Colombia.

Dr. Marta Caceres Dahiya:
I grew up in Colombian, Medellin. Normal family, four kids, very supportive parents in education, we all went to school. I was fortunate to decide for medicine. I had great support and I finished medicine in Colombia. It was great. I then came and did research here in United States with the hope to do my residency in United States and I was able to get first in the program of internal medicine with transition to radiation oncology.

Dr. Daniel Correa:
It sounds like with the support of your family and effort that you've also modeled with your own daughter. You were able to start down that path of medical training, which can be very long. I'm wondering, as you were growing up with your family in Colombia and you advanced through your medical career, how did you envision starting your own family?

Dr. Marta Caceres Dahiya:
I have the dreams that everybody have, to have a healthy kid and that my kid will be able to do many things. I was very fortunate and you want your kids have either your good experience or better experience or given better life than you and things didn't went that way. I mean, my daughter was born and it was a little bit different to what I experienced previously with myself or my siblings or my siblings having kids. It was different to what it was expected.

Dr. Daniel Correa:
Can you take us back to that? How was your pregnancy, delivery, in those first few days, getting to know Sophia?

Dr. Marta Caceres Dahiya:
My pregnancy, I was very happy, but one of the things that I recall was being a physician, I was thinking my kid doesn't move that much when I was pregnant. And that I was like, okay, that was okay and then I have to be induced at 35 weeks because she wasn't growing. And when she was born she was very hypotonic and she didn't want to get fed. She was sleeping all the time. We have to really force her feedings and she wasn't responding like every kid respond. She didn't raise her head when she was supposed to at the three months, she didn't move like she was supposed at the six months. Everything was behind, behind, behind and it was getting more behind. Then that was the transition, all the questions, what is happening? My pediatrician referred me very quick to a neurologist when she was very little and we saw him at three months and he told me, give her three months and see what happens.
At six months, we start therapy. He know that she wasn't progressing like she should and we start initially physical therapy at home and from there adding therapy, so occupational therapy later on, and later on, speech therapy when she wasn't even saying any words. Then everything was very, very delayed. I mean Sophia was able to see that year and a half old by herself. She was able to walk when she was more than two years old. She couldn't crawl at the same time that everybody crawled, couldn't say her words when she was supposed to. She was almost nonverbal and finally she say a few words when she was three years old.

Dr. Daniel Correa:
Well nearly from the beginning you had an awareness that there was something different and you dove in fully into all the treatment and support and therapy to try to help her move forward and she progressed some but still wasn't really meeting those goals or those developmental milestones, as we describe in medicine and we talk with families. As it moved forward, what were the things that started to stand out that seemed to suggest that it was more than just being a little delayed?

Dr. Marta Caceres Dahiya:
Then it was all that delay and the anxiety of being a parent, you know, my kid is not doing what everybody else that I know is doing. One of the pediatricians told me, if you put her in a daycare, she's going to pick up and she's going to get better. And she got kicked out of the daycare when she was less than... She was two years old and I was devastated and the reason for they kicked out was they couldn't handle Sophia and they couldn't handle Sophia because her behavior, she was eloping from everywhere. She was trying to escape from everywhere.
Then I start the program, an early intervention program with the school district. And even with the school district was the same problem. I mean she was very difficult to manage because while they were trying to see all the kids in one place, she was trying to run the other way. She was trying to move the other way. She could escape anything. She will start biting or hitting because she didn't want to stay there. She didn't have any attention. She couldn't have more than 10 seconds of attention on something. She'd start repetitive behaviors. She got one-to-one help at school and not even with that one-to-one, she wasn't really doing well.

Dr. Daniel Correa:
So even being already in a special needs setting and getting some of that additional help, she was even at that stage standing out from her compatriots and other kids there in the class because of these challenging behaviors?

Dr. Marta Caceres Dahiya:
Yes. And at that time there was no manage for that. It was quite difficult. Then I was, I guess, fortunate enough I had a neighbor that she was a psychologist and she had a kid with autism. And because this is kind of an area that unless you have autism, there is no therapy for behaviors, truly, when they're that small. Then she was doing behavioral therapy, ABA.

Dr. Daniel Correa:
Can you describe ABA a little bit more for us?

Dr. Marta Caceres Dahiya:
It's a behavior therapy and what ABA want to do is modify behaviors. They break down the behaviors and ABA tried to get why the kid is doing the behavior and how you can modify, how you can compensate the kid or the kid to the way that you can modify to the behavior that you decide. It has a lot of observation, what is the function of the behavior, why she's doing that, and also how you can modify and how you can get the kid engaged to modify their behavior.
I start ABA with therapy at home and that intervention really has helped a lot. It was the only thing that got Sophia from even having been able to pay attention to more than 10 seconds to be sitting in a room, now she's able to watch a movie. But it's a very long road. I was fortunate enough that I found it and I was able to do this by myself with the family but you need a diagnosis of autism to get the insurance to pay for.

Dr. Daniel Correa:
And it sounds like quite a challenging therapy to go through either way, it's really an involved communication process.

Dr. Marta Caceres Dahiya:
And a good ABA therapy program for somebody, at least like my daughter with severe intellectual disability, you have to do more than 40 hours a week to make it work.

Dr. Daniel Correa:
How is it that you came to know about Sophia's genetic diagnosis with SynGAP, where did that come from?

Dr. Marta Caceres Dahiya:
At the time when we were in San Antonio I had a great, great neurologist, and he always was very open to everything and he tried everything. Everything we thought about, every test and then when the genomic testing came commercial, that's when he referred me to genetics and I was referred and I got the whole exam sequencing. And we got what is called a trio that is very important in this genetic encephalopathies that you get the father, the mother and the kid just to prove if there is hereditary or is the novel.
Then most of the cases on SYNGAP, like Sophia, that's how I got, but that was when Sophia was 10 years old that we got the diagnosis. Then we didn't know what was going on with her since then. Retrospectively at that time we found that she was having seizures but there were so mild that I that we didn't know that they were seizures. We didn't know where all that was coming from. Then it was very helpful to know the diagnosis.

Dr. Daniel Correa:
Once you had a sense that there were seizures, they're so subtle and difficult to even have noticed at first or to notice when they're occurring. And you brought up whole exome sequencing and that's sort of there's differences in types of genetic tests and that has been increasingly accessible to people but sometimes still very challenging. I know the SRF has made some extra efforts to help people get access to the testing that really more specifically tells them information about the genetics of their condition. Can you tell us some about those efforts and how families might be able to get access to that testing?

Dr. Marta Caceres Dahiya:
We did something online, answer a questionnaire that could be SYNGAP, and then you answer the questions and if the questions show that it's probably SYNGAP, you get testing for free. We has been associated with different companies that can test for free, and right now really there is no excuse to don't get exome testing or genome testing because a lot of companies are doing it for free.
I was recently just in December on the AES, and really now the American Epilepsy Society is recommending go straight for the big test like the exome sequencing or genome sequencing. You can miss a, not just SYNGAP, you can miss a lot of other things that can help people. You don't imagine how different in is life after you know the diagnosis and you can tell to you and your family and everybody's helping you with your kid, it wasn't that you wasn't doing enough. This is the disease and it's so different to have a community that lives what you are living and can tell you, yeah, this is a seizure, this is not a seizure, because everything is better sometimes, or can tell you this is the way you get services.
It's gigantic, it just gives you so much peace of mind, so much help. The family life have to change so much and have to adapt so much, that is very important to know best practice and it's very helpful to the clinicians I have by now, like you said, you go and you cannot help the clinicians to get more educated about it and they're grateful because they can do something better for your patients. Then it's being associated with organization, find your diagnosis is so important.

Dr. Daniel Correa:
If nothing else, it's empowering and validating in many ways that the information and the testing. Now Marta, you've been working with the SRF really to help support, increase awareness, increase research funding and also research participation. Can you tell us about the activities that you've participated with them?

Dr. Marta Caceres Dahiya:
We do webinars and the webinars can be very scientific and can be with the new genetic therapies that are coming or the models that we are creating or anything like that. Just helping the families to educate them better, to find resources. We have a scientific board that help us to make decisions regarding all the basic science that we help to plan and we help to have resources for and we have a clinical board. Then I manage more the part of the clinical part because that's, I think, my strength in being a physician.
We have been able to do medical considerations for SYNGAP because it's so different to manage SYNGAP kits to help clinicians to have a diagnosed and what is important, what is not important and all these considerations have been reviewed by our medical board, is more than 15 clinicians that have reviewed and they're all at on SYNGAP.

Dr. Daniel Correa:
If you could go back, what reassuring words would you offer to young Marta, a young mother, starting down that path?

Dr. Marta Caceres Dahiya:
I will say that if I go back, I would say that yes, Sophia and there is very much enjoy moments with her and she's love and life gets better. Life gets better. You always can find activities that you can find enjoyment together. I would say that if I was strong get also and at that time there was that parent that I could find, a parent community, I think that would be so helpful. I didn't because she wasn't diagnosed until she was 10. And at the time she was diagnosed there was only 13 reported cases in the world, now we have almost 1200. Then I think that sense of community is very helpful.

Dr. Daniel Correa:
Oh, Marta, thank you so much for sharing yours and Sophia's story and journey together and all that you're doing with the SRF to help other families and to build a community to work towards a future cure and families living better with this medical condition.

Dr. Marta Caceres Dahiya:
Thank you so much for having us. It's amazing to be able to talk about the disease and to be able to talk to other people and other clinicians about how they can help the communities of epileptic encephalopathies and we really appreciate you are giving us this window to say our story, to tell our story.

Dr. Daniel Correa:
And now I'm joined with Dr. Angel Aledo Serrano. We're going international. He's from Vitas Madrid Neuroscience Institute in Spain. And Dr. Angel Aledo Serrano is a neurologist and researcher, helping us make advancements in understanding about many conditions including epilepsy surgery, epileptic and developmental encephalopathies and the genetics of different rare epilepsies.
And he's also involved in various clinical trials for different genetic epilepsies, including the condition we're talking about today, SYNGAP1. If you want more information about all the different things he's doing work on and helping also understand the various neurologic conditions that he works with, he's also active on social media as @AledoNeuro and works also in support of various health organizations. Aledo, thank you so much for taking the time to join us here.

Dr. Angel Aledo Serrano:
Thanks for having me. It's a real pleasure to be here.

Dr. Daniel Correa:
So in our episode series we talked to Paulina Polanco, a sister and full-time care partner for her twin sisters, Libby and Espy, and we talked to Dr. Marta Caceres, a radiation oncologist, but also the mother and caregiver of her daughter Sophia. They all have different stories and sometimes even different symptoms. So Aled, can you help us understand what we know about SYNGAP1.

Dr. Angel Aledo Serrano:
SYNGAP1 encephalopathy is a condition we call neurogenetic. So it's a genetic condition with neurologic symptoms. We call the general umbrella where SYNGAP1 is included developmental and epileptic encephalopathies. They are a group of conditions where the affected people have symptoms associated with neurodevelopmental problems, so intellectual disability, autism spectrum disorders, behavioral disorders, gastrointestinal problems, sleep comorbidities, so many symptoms which are related to a mutation in SYNGAP1. SYNGAP1 is a gene which is encoding a protein which is really important for the function of the brain. So when we have this mutation, which is the novel means that this mutation is new in the person who is suffering, this is in the 90% of the cases, this is not inherited from the parents and that's important. This mutation is causing all the symptoms.

Dr. Daniel Correa:
So then it's new in the person in their family, they didn't inherit it directly from their parents or from a grandparent. Do we know the likelihood of another family member or child in that family being born with SynGAP1?

Dr. Angel Aledo Serrano:
So normally when it is the novel and this is 90% of the cases, normally the chances are very, very, very unlikely to happen because it's not related to the previous generation. So normally we have 40 new mutations compared to our parents, all of us, and if you are unlucky enough to have this mutation in SYNGAP1 or in any other gene related to a neurodevelopmental disease, then you have the condition.

Dr. Daniel Correa:
So then of course the question is really how many people have a SynYNGAP1 variant or dysfunction?

Dr. Angel Aledo Serrano:
So this is something we don't know exactly, and this is something we are starting to know in the last few years. This is because there is, what we call, under-diagnosis. So a lot of people with SYNGAP1, they are out there without a proper diagnosis. So what is estimated is that one in every 10,000 people have SYNGAP1. That makes that single one is one of the most common rare diseases. So it's still a rare disease but is one of the most common among them.

Dr. Daniel Correa:
And being one of the most common, then it raises sort of the question, how is it different from some of the other genetic conditions that are associated with intellectual disability or seizures. I'm thinking for example, Fragile X, Angelman and Rett syndrome are also other genetic conditions that have intellectual disability.

Dr. Angel Aledo Serrano:
So classically, we were thinking about traditional syndromes, which are some symptoms like this kind of scissor or this kind of electroencephalographic abnormality or this kind of autism spectrum disorder. And then we tried to see which specific genes were related to these syndromes. Thinking like this, normally there are two epilepsy syndromes which are related to SYNGAP1. One is doose syndrome, doose syndrome, which is myoclonic aesthetic epilepsy. This is an epilepsy with myoclonic seizures. Myoclonic seizures are seizures with jerkins in extremities and also in the trunk in the body. But also with drop attacks and we see this both seizures in SYNGAP1.
The other one is what we call Devon's syndrome, which is also a classical name. This syndrome is related to absences of seizures, seizures with some disconnection from the environment, related to also eyelid myoclonia, which is blinking all the time, at the same time of the absence.
So both epileptic syndromes are the most common in SYNGAP1, and this is different from other genetic disorders with seizures. Also, the kind of autism also the kind of intellectual disability, all these are somehow a specific of SYNGAP1, but not too specific. And because of that, when we are asking for a genetic testing trying to find a genetic condition as like SYNGAP1, we cannot perform one gene test. We have to perform a panel with a lot of genes or an exome sequencing with all the genes, because it's not so specific. You never ask for only SYNGAP1 gene, that's not so common.

Dr. Daniel Correa:
Something that we're both very aware of that even though we use these terms or these names and they have some symptoms or syndromic or that characteristics that might be similar among many people living with it, that each person is unique and we have to really consider the category they fit in when we consider all the different testing. And hopefully more people will have more comprehensive genetic testing.

Dr. Angel Aledo Serrano:
Absolutely, and we are still discovering this, we are what we call expanding the phenotype. So understanding that, for example, there are some milder cases of SYNGAP1 with only mild intellectual disability or mild autism traits. And in the past we were not performing genetic testing for these people and now that we are doing that, we are seeing that some of them, they have milder forms of SYNGAP1. So this is work in progress.

Dr. Daniel Correa:
Genetic testing is not easy sometimes to get and it's also can be expensive. So why would it be important for a person and their family to have some understanding and information about the genetics of their condition?

Dr. Angel Aledo Serrano:
Knowledge is power, so we have to know, we have to put a name. Sometimes we have to take out the shame and the responsibility of the families because sometimes the families think that the problem is related to the delivery, so we know this is not the case for the majority of them. So only for that, that's very, very useful, to put a new level and taking out this responsibility.
Sometimes in a lot of conditions, and we are seeing this with Singapore, but also with Dravet syndromes, they can join a patient advocacy group. That's very, very useful for them to belong to a community. And also have a name in the sense of knowing more about the prognosis, about the complications, about the symptoms in the future. Sometimes we have what we call precision medicine. There are some types of anti-seizure medications or medications for sleep or for behavioral problems which are more specific or work better in a specific condition. And also sometimes we can provide an inclusion in a clinical trial. If we have a specific diagnosis, we can send the patient to another center for a clinical trial specific for their mutation. So that's some of the good things about genetic testing in general.

Dr. Daniel Correa:
In our stories and from their families, heard Libby and Espy weren't even diagnosed with SYNGAP1 until they were age 17. Is this a typical delay?

Dr. Angel Aledo Serrano:
So this is what we call the diagnostic gap. The diagnostic gap is too big still, and I think we are improving and this diagnostic gap is worse in adolescents and also in adults. This is, I think the same in the US and in Europe. In Spain, we published a paper just two years ago trying to see which proportion of patients were under a study and underdiagnosed, for example, patients with intellectual disability and epilepsy that they were not offered any genetic testing or video EEG or MRI and neuroimaging. This proportion is very big in adults. So it's lower in children. So I think we are improving, but sometimes we have to empower the families and to push them to talk to their clinicians and ask for genetic testing.

Dr. Daniel Correa:
And for each of the girls from the families that we spoke to, a lot of them were initially diagnosed as autism. Is this common among people diagnosed with SYNGAP1?

Dr. Angel Aledo Serrano:
Yeah, this is something I guess it will change in the future, but for now we are leveling symptoms, specific symptoms, like autism or intellectual disability or epilepsy. And sometimes there are clinicians who are stopping in that level and they use only autism as a final diagnosis.
But what we know is that autism is not a disease, it's an umbrella concept, and inside this concept we have a lot of different diseases and one of them is SYNGAP. It would be the same for developmental epileptic encephalopathies or intellectual disability. We know that they are symptoms or group of diseases with similar symptoms. So what we have to do is to perform genetic testing in all these general symptoms and be more specific in the diagnosis to know the cause of the autism or the intellectual disability.

Dr. Daniel Correa:
When should families seek testing for SYNGAP1 or for a genetic cause of autism or epilepsy? What raises that red flag to say, oh, they should be asking for it if it hasn't been already done, or maybe asking what types of tests they've had done?

Dr. Angel Aledo Serrano:
This threshold to ask for a genetic testing is changing. So in the past we were only doing genetic testing when refractory seizures were associated with intellectual disability or autism spectrum disorders. But now we know that some drug responsive epilepsies, so some epilepsies where seizures can be controlled with medications, we know that they can have a genetic condition. So normally we will ask for a genetic test when the seizures are starting earlier in life, so in the first six years of life. In those cases we know that a genetic condition is underlying the epilepsy in 50, 70% of the cases.
Also, when there is an autism spectrum disorder, combined with the seizures or alone, and this is important because in the past only when seizures were present we were performing genetics testing. Now we know that a lot of people with SYNGAP1, they have only autism traits or intellectual disability. So in both cases what we call neurodevelopmental disorder, so there's some symptom of a development which is not going okay. In those cases we should perform a genetic testing. And which kind of genetic testing, so the perfect one for now will be an exome sequencing. Probably in the future we will have more of genome sequencing, but for now what is normal clinical practice is exome sequencing, or even better, trio exon sequencing, which is also sequencing the parents.

Dr. Daniel Correa:
With the families we spoke with, we saw a difference in when seizures might show up. Espy didn't have seizures recognized until she was 19. Amelia had them as a young child. What do we know about the timing of seizures or if they show up at all in SYNGAP diagnosis?

Dr. Angel Aledo Serrano:
Yeah, so this is very heterogeneous. It's very different in every person with SYNGAP1. Some of them they have seizures very, very early in life and some of them they are starting later. But what is important in this regard is to have in mind that sometimes when you see the first seizure very easily from the outside, sometimes seizures started way before. And how can we catch them? We have to perform video electroencephalography, video EEG. And the problem is that healthcare systems, sometimes they only provide video EEG for 30 minutes or one hour. I don't know how it's commonly in the US, but in Europe it's difficult to get sometimes for the families a long video EEG. And we know that if you don't perform a six hours or 12 hours, or even better 24 hours, so having sleep at night, daytime, different routines and different situations, sometimes you don't see, for example, mild absences or mild seizures during sleep. So it's important in SYNGAP1 and in other neurodevelopmental conditions to perform video EEG monitoring.

Dr. Daniel Correa:
Yeah, this is something we do regularly at our center at Albert Einstein in Montefiore. And many patients, families, young children are brought in to stay at night even if they don't clearly have seizures to make sure they're not having them at night, or when they wake up during the night or when they're interacting with their family, maybe no one even noticed.
Wow, I am touched by the stories that the families shared and by Dr. Aledo Serrano's input on really the experience he's had both in the research but in helping families with treatment. And we're not done. Of course, every person in family are unique, but with SYNGAP1, the experience of each family with their loved ones can be quite unique. So we will continue our discussion and stay tuned for next week to hear from Vicky Artiega to share her daughter Amelia's story, and more from Dr. Aledo Serrano about SYNGAP1 and the science behind this and other rare epilepsies.
Thank you again for joining us today on the Brain & Life podcast. Follow and subscribe to this podcast so you don't miss our weekly episodes. You can also sign up to receive the Brain & Life magazine for free at brainandlife.org, and even get the Espanol version.
For each episode, you can find out how to connect with our team and our guests along with great resources in our show notes. We love it when we hear your ideas or questions. You can send these in by email to BLpodcast@brainandlife.org and leave us a message at (612) 928-6206. You can also follow the Brain & Life magazine and me on any of your preferred social media channels.
These episodes would not be possible without the Brain & Life podcast team, including Nicole Lussier, our Public Engagement Program Manager, Rachel Coleman, our Public Engagement Coordinator and Twin Cities Sound, our audio editing partner.
I'm your host, Dr. Daniel Correa, connecting with you from New York City and online @NeuroDrCorrea. Most importantly, thanks to our community members that trust us with their health and everyone living with neurologic conditions. We hope together we can take steps to better brain health and each thrive with our own abilities every day. Before you start the next episode, we would appreciate it if you could give us five stars and leave a review. This helps others find the Brain & Life podcast. See you next week.

Part One: Community Stories of Navigating a Rare Epilepsy Diagnosis

Additional Resources

Follow us!

Episode Transcript