How a Neuroscientist’s Genetic Discovery Treated Her Daughter’s Epilepsy

One night in 1995, Tracy Dixon-Salazar, then a stay-at-home mom, put her two-and-a-half-year-old, Savannah, to bed as usual. But in the middle of the night, Savannah, who had been reaching all of her developmental milestones until then, had her first seizure.

While her seizures occurred on-and-off initially, they returned with full force six months later. “She would go on to have 50 to 100 seizures a day, seizing every single day until she was 18 years old,” recalled Dixon-Salazar.

When she was five, doctors diagnosed Savannah with Lennox-Gastaut Syndrome (LGS), a severe form of pediatric epilepsy that can lead to impaired intellectual functioning and developmental delays.¹ While a number of LGS cases are linked to structural brain differences caused by a brain injury or infection, Savannah had neither, perplexing her doctors and parents. That is when Dixon-Salazar decided to take matters into her own hands.

In the beginning, no one could really tell me why. Why did I have this healthy kid, and then all of a sudden, her life was completely derailed?

—– Tracy Dixon-Salazar, LGS Foundation

Over the next 15 years, she completed her bachelor’s degree, PhD, and a postdoctoral fellowship in neurogenetics. Dixon-Salazar identified a genetic cause underlying Savannah’s condition, helping guide her treatment that reduced her seizures by 95 percent. Although Savannah passed away at the age of 31 last year, Dixon-Salazar’s efforts significantly improved her quality of life for 11 years. In addition to helping her daughter, Dixon-Salazar also discovered several genes linked to other pediatric neurodevelopmental conditions. Today, as the President and CEO of the LGS Foundation, a non-profit organization powering LGS research to improve lives, Dixon-Salazar bridges the gap between preclinical research, clinical treatments, and patient advocacy to help those living with LGS.

From English Class to Modeling Epilepsy in the Lab

When Savannah started having recurrent seizures in 1996 at the age of three, doctors were initially stumped despite tests and scans. “In the beginning, no one could really tell me why,” said Dixon-Salazar. “Why did I have this healthy kid, and then all of a sudden, her life was completely derailed?”

As someone who had been an average high-school performer, Dixon-Salazar started visiting a local library to look up what it meant to have seizures. Savannah’s LGS diagnosis pushed her to learn more about epilepsies.

Around this time, she stumbled upon a paper about genetics and epilepsy but did not understand anything written in it. “And so, I thought, ‘I have to go to college and take English classes,’” she said. But scoring top grades in her English class did not help her read the paper, leading her to a realization. “The paper was not in English. It was in science and medicine,” she said. “Those two things aren't even the same language.”

So, she signed up for her first science class. “And I just fell in love with it,” she said. “Science and studying became my therapy. It became my way of dealing with this horrible thing that was happening. So, every time she would have a seizure, I would go study… So, of course, I was an amazing student because I was studying all the time.”

It was during her science classes that Dixon-Salazar first learned about genetics and its role in epilepsy and neurodevelopmental disorders. This prompted her to intern in neurogeneticist Joseph Gleeson’s lab at the University of California, San Diego (UCSD). Her lab mates told her about graduate programs that offered a scholarship, prompting her to apply to different schools in San Diego for her PhD.

She eventually enrolled in a PhD program at UCSD around the time that Savannah hit puberty. Taking care of her sick daughter while also pursuing graduate studies proved to be a monumental challenge. Wanting to finish her studies quickly, Dixon-Salazar worked 80-hour weeks and completed her PhD in four and a half years. Soon after, she joined Gleeson’s lab as a postdoctoral fellow.

By this time, Savannah’s seizures had shot up to nearly 300 a month. She would sleep for 18 hours a day and functioned at the level of a three-year-old. She was on seven different medications, had a vagus nerve stimulator implanted through surgery, and often received emergency rescue medicine to stop seizures that would not stop on their own. Dixon-Salazar and her husband played tag-team taking care of Savannah and going to work, with the former often sleeping in her car to take care of her stem cells and organoids in the lab.

Through it all, people often advised her to slow down. “The mentality back then was, ‘Go home and love her because she's going to die, and so just enjoy your last days with her,’” said Dixon-Salazar. But she refused to accept this. “I very much enjoyed all of my days with her, but I [said], ‘No, I'm not going to settle for that.’”

Optimizing the Genomic Pipeline

As a postdoctoral researcher, Dixon-Salazar’s work involved using next-generation sequencing to identify potentially pathogenic mutations in samples of children suffering from epilepsy. She would then model these mutations in animals and human stem cells to pinpoint the mechanisms driving phenotypic changes. “She was so motivated to learn as much as she could because for her it was very personal,” said Gleeson. “She was decoding the genomes of many, many other patients with epilepsy.”

Through her work, Dixon-Salazar carried out exome sequencing and perfected the bioinformatics pipeline to analyze the results. By applying this to a cohort of more than 100 people with neurodevelopmental disease, Dixon-Salazar, Gleeson, and their team identified a number of mutations underlying the condition.² Their work brought genes that had never been linked with disease into the spotlight.

For instance, the researchers identified mutations in exocyst complex component 8, a gene encoding a protein that plays a crucial role in facilitating exocytosis, in a boy with Joubert syndrome, a rare genetic disorder. Their findings also implicated the gene encoding ribosome-releasing factor 2, a mitochondrial protein responsible for disassembling ribosomes at the end of translation, in microcephaly.

It was miraculous. If you had told me that drug number 27 was going to make a difference, I would have not believed you.

—Tracy Dixon-Salazar, LGS Foundation

In this manner, Dixon-Salazar, Gleeson and their colleagues identified new genetic markers for neurodevelopmental diseases. Their findings also indicated the utility of exome sequencing to improve diagnosis and guide treatments in people with neurodevelopmental disorders.

“It was very exciting at that time because this was a brand-new way of doing this in a very high-throughput way. Now we could solve these conditions for the first time,” said Gleeson. But none of the new genes Dixon-Salazar helped identify could explain Savannah’s LGS. “Her family was not in that publication, her own child,” he said.

It was around this time that Gleeson enquired how Savannah was doing. “And I burst into tears,” recalled Dixon-Salazar. “And then he said, ‘We should sequence her.’”

So, she, her husband, and Savannah submitted their samples, which the researchers sequenced. Tasked with analyzing the results, Dixon-Salazar pored over the sequences “day after day,” recalled Gleeson. “You can imagine how personal it was for her.”

The Miracle of Drug Number 27

For nearly one year, Dixon-Salazar analyzed Savannah’s exome sequencing results through the bioinformatic analysis pipeline she had optimized. She eventually identified several hundred genetic variants that Savannah carried. Filtering further revealed about 25 mutations in a group of genes encoding calcium signaling-associated proteins, including de novo mutations in the L-type calcium channels that regulate calcium entry into neurons.³

Realizing that Savannah’s brain cells were being pumped with too much calcium prompted Dixon-Salazar to propose treating Savannah with verapamil, a calcium channel blocker commonly used to treat high blood pressure and other heart conditions. “That was a very creative kind of solution,” said Gleeson. “That was something nobody had attempted.”

While it made sense to him from a genetic standpoint, Savannah’s epileptologist was apprehensive at first. However, after already having tried 26 drugs that did not help, he agreed to treat Savannah with a low dose of verapamil. Almost immediately, the frequency of Savannah’s seizures reduced.

“It was miraculous. If you had told me that drug number 27 was going to make a difference, I would have not believed you,” said Dixon-Salazar. “And I have never been so happy to be wrong about some…things because I was so wrong. Drug number 27 changed our lives for 11 years.”

Until then, Savannah had suffered from more than 40,000 seizures, which affected her neuronal functions. When verapamil finally reduced her seizures, the doctors removed the implanted neurostimulator and reduced her medication. She also started learning and eventually operated at the level of a seven- or eight-year-old in certain skills. “She started talking and sassing,” recalled Dixon-Salazar. “She was so bossy!”

For more than a decade, Dixon-Salazar’s efforts helped reduce Savannah’s seizures from 300 a month to about 25. However, last year, her seizures returned after suffering from long COVID, and she passed away from a fatal seizure during her sleep. Just a month shy of turning 32, Savannah lived a much longer life than most medical textbooks and doctors had predicted.

While Savannah’s passing shook her family and the LGS community, Dixon-Salazar does not believe that it takes away from the life Savannah got to live or dampens her story. “I can now look back and say, ‘Yes I did make a really significant contribution to her life and to science on a certain level,’” Dixon-Salazar said.

Bridging the Information and Treatment Gap for LGS Families and Researchers

As a neurogeneticist with lived experience of caring for someone with epilepsy, Dixon-Salazar had unique insights into the condition. She authored a number of publications not only about the genetic variations underlying epilepsies and exome sequencing pipelines, but also about the psychosocial impact of caring for children with developmental disorders.^4,5

Realizing the need to take preclinical studies to the clinic, Dixon-Salazar joined the LGS Foundation as the Director of Research in 2017, where she helped to identify and push forward essential research. Today, as the President and CEO of the foundation, she oversees research programs and patient databases, guides clinical trial designs, and has also established the LGS exome project, bringing genetic testing to the families who need it.

As part of her work at the LGS Foundation, Dixon-Salazar frequently participates in meetings and facilitates dialogue between the various stakeholders in the LGS field. “Tracy is very good at bringing scientists and clinicians with very different scopes of expertise to all work together,” said Jennifer Gelinas, a pediatric epileptologist and scientist at the University of California, Irvine.

Gelinas first met Dixon-Salazar at a conference in 2014. “I remember that she was so incredibly passionate, and motivated, and driven,” said Gelinas. Over the past few years, Gelinas has not only followed Dixon-Salazar’s work, but also worked with her as a science advisory council member at the LGS Foundation.

“She has been really transformative in terms of helping patients and families to understand their diagnosis, to know what options are available to them, [and] to have a sense of agency and ownership,” said Gelinas. “That helps so much with what is typically a very difficult journey.”

It is the drive to help other families that keeps Dixon-Salazar going, even after losing Savannah. Going back to work was not easy, she said. “But I decided to stay at the foundation…and just keep fighting for the families in her honor.”

Looking back, Dixon-Salazar said she never went to college with the hope of finding a treatment for Savannah; she just wanted to understand what was happening. “I'm honored…to have had a hand in extending her life and giving her a beautiful life,” she said. “I still wrestle with believing it.”

She also feels honored to see how far the fields of epilepsy and LGS research and care have come. Today, scientists have linked more than 1,500 genes with epilepsy.⁶ “When I started in this space, there were four,” remarked Dixon-Salazar.

This advance has not only transformed genetic screening strategies, but also helped revolutionize treatment options, including gene therapies.⁷ “If you can say that in a lifetime, you saw a disease [where people said], ‘Go home, love your child, there’s nothing we can do,’ to ‘Oh my gosh, we actually understand a ton about it,’ and you had a small hand in that…I think you can sleep well with that,” said Dixon-Salazar.