Collins, Thomas R.
ARTICLE IN BRIEF
A neuroscientist describes her journey to ameliorate the seizures in her daughter's Lennox-Gastaut syndrome.
Figure. DR. TRACY DI...Image Tools
Tracy Dixon-Salazar, PhD, held her audience captive last October when she took to the lectern for a featured plenary at the American Neurological Association annual meeting. The associate research director at Citizens United for Research in Epilepsy (CURE) had come to talk about her research at the University of California, San Diego (UCSD), which had led to the identification of gene abnormalities in a patient with Lennox-Gastaut syndrome, a form of epilepsy that starts in childhood. And she had encouraging news — treatment with a calcium-channel blocker had reduced seizures in that patient from 300 a month to 20.
But this was no ordinary patient — it was her daughter Savannah. And her journey to find some answers to a basic and clinical problem was decidedly personal and a non-traditional one at that.
It had begun years earlier with a call to 911. Then, the 23-year-old stay-at-home mother — a high school graduate who had spent time in the Navy — was bewildered when the paramedics who rushed her toddler to the hospital told her that her daughter was having seizures.
Shortly after that day, Savannah had a few seizures, but then, for six months, she had none. But around the time of her third birthday, Savannah's epilepsy manifested itself with a vengeance, with more frequent and more prolonged seizures. She was diagnosed with Lennox-Gastaut syndrome.
Treatments were nearly useless — one after another was tried and didn't work. Frustrated, the mother scoured the medical literature — or tried to anyway. It was over her head. She thought she just needed to expand her vocabulary with some college coursework in English. She enrolled, and did well in those classes at a junior college. But it didn't help much with understanding the journal studies. She needed to take some science, too. Up until then, her interest in science amounted to “none whatsoever.”
“Biology was my least favorite class in high school,” she said.
But this time — with, to say the least, a new perspective — she “fell in love with science.”
“I knew the answers to the questions I was seeking were in medicine and science,” Dr. Dixon-Salazar said.
So, she set out to get her associate's, then her bachelor's degree — paid for with scholarships. At first, she said, she operated on the assumption that, once family obligations demanded it, she would cease her coursework. After a while, though, she began to wonder whether she'd be capable of giving school up, eventually realizing that she was in it for the long haul.
With a supportive husband and son — who accommodated her absence while she attended class and studied — she plowed through. It was a grind and the schedule was difficult, but her education was also an outlet, and a breather, she said.
“I think school saved me,” she said. “Any parent who has a very severely affected child needs to have something outside of that” — whether it's volunteering or hosting a blog.
She eventually got her master's and a PhD, with a dissertation on the role of immune molecules in normal brain development and plasticity.
RESULTS OF EXOME SEQUENCING
As a post-doc, she began to do exome sequencing with Joseph Gleeson, MD, professor of neurogenetics at UCSD. Dr. Gleeson recruited patients with neurological disorders and sequenced their exomes, looking for gene abnormalities that might offer a clue to treatment for their diseases. Originally he wasn't recruiting epilepsy patients, but he began to recruit patients and their families with inherited forms when Dr. Dixon-Salazar began working in his neurogenetics lab — because, as she put it, he's “a good guy.”
Dr. Dixon-Salazar said she thought about the possibility of Savannah being sequenced, but didn't want her to interfere with the work involving the other patients and families. By that time, about two and a half years ago, Savannah's epilepsy had gotten “exponentially worse,” Dr. Dixon-Salazar said.
Dr. Gleeson asked whether she might want Savannah to be sequenced, and Dr. Dixon-Salazar jumped at the chance.
The lab had sequenced several hundred patients a year, and occasionally — but certainly not always — gene mutations were found that led to treatment choices that made a clinical difference. But at least it was a shot.
“Even if you don't find the actual causative gene you can identify driver genes that are having a stronger effect,” Dr. Dixon-Salazar said. “They may not be the domino that's holding it all together, but that's really driving it. If you can somehow regulate that, maybe you can put the brakes on the severity.”
Sequencing of an exome generally reveals about 100,000 variants. That's filtered down very quickly through processes that have been commercialized.
In Savannah's exome, 300 variants were found that were rare and unique to her, and that were predictive of damage at the protein level and not found in healthy people. In other words, they were “high impact” genetic changes, Dr. Dixon-Salazar said.
Those 300 were fed into several analysis paradigms. And the one that yielded the most insight was that which grouped them by function.
They found 25 mutations in the calcium-signaling pathway. And 14 were in calcium-channel genes, the subunits that actually come together to make the calcium channels, which are grouped according to the amount of calcium they let in at a given time. Of those, six were related to the L-type channel. An assessment was made on the effect those variants were likely having on Savannah's calcium intake. This was a jolt to Dr. Dixon-Salazar: She had always noticed that when Savannah received calcium supplements — a standard of care because antiepileptic drugs (AEDs) are known to inhibit the ability to absorb calcium — her seizures got worse. But now, it appeared that Savannah might be genetically programmed to allow too much calcium in through those channels.
So what about verapamil, a calcium-channel blocker to the types of channels that appeared to be most affected in Savannah? The idea was discussed with her pediatric neurologist, Mark Nespeca, MD — and, although it was novel in this setting, they figured it couldn't be any worse than any of the other treatments that had failed.
Within a month, Dr. Dixon-Salazar saw dramatic change in her daughter. The number of seizures were reduced by a nearly 95 percent drop. And those that remained were all nocturnal — with less chance of injury. Savannah is now off two AEDs, and a third has been cut in half.
Whether due to lessening of the epilepsy itself, or because the side effects have lessened because she's on fewer medications, Savannah has become more talkative, more expressive — and, to her family, more knowable.
She and her parents don't have to rely on silly noises to communicate with Savannah, who is now 20. Much less of her time is spent unconscious.
“It's kind of sad but I feel like we're getting to know her for the first time,” Dr. Dixon-Salazar said.
Shortly after she began to improve on the verapamil, Savannah one night marched out of her bedroom into the living room and issued an order to her father.
“Dad, you have three minutes to turn off the TV and come to bed because it's bedtime,” Savannah told him. The moment was remarkable both for the number of words Savannah strung together clearly, and because she was confident enough to leave her bedroom on her own without the protection of a helmet.
“This was a huge immediate effect,” Dr. Dixon-Salazar said.
Dr. Nespeca, clinical professor of neuroscience at UCSD and director of the EEG Laboratory at Rady Children's Hospital, said that Dr. Dixon-Salazar's accomplishments stem from a “tremendous energy and commitment and enthusiasm.”
One of the first times he met her was at a Kids Speak Up program with the San Diego chapter of the Epilepsy Foundation, in which children and parents lobby Congress for more epilepsy funding. Dr. Dixon-Salazar brought a glass jar filled with all the medications she had to give her daughter every day to show the struggle of dealing with the intractable disease.
“That spoke volumes to any legislative assistant or congressman,” Dr. Nespeca said.
Dr. Dixon-Salazar said that she is confident that the use of pharmacogenetics can become more widespread so that more people can benefit, even if there's some risk. “Being completely risk averse isn't going to get us where we need to be,” she said. “But at the same time, being careful to back it with science, I think, is important.”
TUNE IN, JOIN THE DIALOGUE: How did a neuroscientist ameliorate seizures in her daughter's Lennox-Gastaut syndrome? In this video segment, Neurology Today Editor-in-chief Steven P. Ringel, MD, talks with Tracy Dixon-Salazar, PhD, associate research director at Citizens United for Research in Epilepsy, about her journey from being a stay-at-home mom to going back to school — earning an associate's, bachelor's, master's, and finally a PhD in neurobiology at University of California, San Diego — that led her to sequencing and identifying mutations in her daughter Savannah and finding an off-label treatment, verapamil (a calcium channel blocker) that helped reduce her daughter's seizures by 95 percent: http://bit.ly/XgS6E5.
LINK UP FOR MORE INFORMATION: