Dante Bergskaug started seizing soon after he was born. He had a rare condition called hemimegalencephaly—the entire right side of his brain was enlarged and malformed. He had unusually severe epilepsy, and his doctors gave him a grim prognosis, telling his parents he probably wouldn’t live to the age of 2.
Peter Black, MD, then chief of Neurosurgery at Boston Children’s Hospital, thought otherwise. “He said, ‘I see him running around outside your house, playing ball with you,’” recalls Dante’s mother Gina.
In 2003, at just 5 months of age, Dante had a hemispherectomy, or complete removal of the abnormal half of his brain. There was little to be found about the operation on the Internet, and the few families with hemimegalencephaly that the Bergskaugs knew had refused surgery. But the decision wasn’t a hard one to make.
“Every day he would have 300 seizures,” Gina says. “The medications would fail one after another. He was hardly able to eat, was really not living the life you’d want for your child. If there was any hope to put an end to this, then we were going do it.”
Dante’s seizures dropped off sharply after the operation. The Bergskaugs donated some of his brain tissue to research, and from time to time met with a young epileptologist and research fellow, Annapurna Poduri, MD, MPH, who was doing genetic studies on the tissue and had lots of questions.
“I would see kids going in for epilepsy surgery who had clearly malformed brains—from small, focal malformations to dramatic malformations of an entire hemisphere,” says Poduri. “For most of them, we still don’t have an answer to the fundamental question of why they have epilepsy, other than a theory that it’s something about the way that piece of brain developed.”
Poduri joined the laboratory of Christopher Walsh, MD, PhD, to pursue these questions. Eventually, she gathered enough hemimegalencephaly cases—eight—to identify a genetic cause.
It was truly a needle in a haystack. All eight children had normal blood DNA tests. But three of the children’s brains had a genetic abnormality, affecting a gene called AKT3—in one case, a mutation in the gene, and in two children, an extra copy of the whole chromosome arm that contained the gene.
To make things more complicated, the defect didn’t occur uniformly in every brain cell. “It’s a mosaic pattern—affecting about a third of the cells,” says Poduri.
Happily for the Bergskaugs, Dante’s is a one-off mutation, not an inherited one. How it causes epilepsy, though, is still a mystery. AKT3 turns on early in the brain’s development and seems to regulate its growth. The brains Poduri and the surgeons were seeing had formed abnormally—from the structure of the brain’s folds and layers to the white matter that insulates nerve fibers and the shape and orientation of individual cells.
Perhaps these structural changes throw off the brain’s electrical function, tipping it toward seizures. Or perhaps AKT3 activates other biological pathways that specifically trigger epilepsy. If those could be found, along with drugs to block them, maybe surgery wouldn’t be needed.
Poduri, and the Epilepsy Genetics Program at Boston Children’s that she now heads, is still investigating hemimegalencephaly—along with a variety of other epilepsy conditions. Recently, Poduri and colleagues found a tiny chromosome deletion in an infant with yet another early-onset epilepsy, known as malignant migrating partial seizures in infancy (MMPEI); within that deletion lies a gene called PLCB1 that is known to turn on during brain development. And at this writing, nine families have enrolled in a study of Ohtahara syndrome, another rare epilepsy that begins shortly after birth.
And then there’s a completely different kind of epilepsy mystery: one involving a family whose ancestors relocated to Massachusetts from a relatively isolated island off the Irish coast. Boston Children’s neurosurgeon Joseph Madsen, MD, operated on the patriarch of the family, who urged other family members to help researchers study the reason for his epilepsy. Madsen also connected the family with Poduri and her team, who contacted family members to gauge their interest.
“The first step is starting the conversation,” Poduri says. “Now that we know they are interested, we are grateful for the opportunity to talk with them more and to see if there is a broader family history that might inform the genetic studies.”
For these projects, Poduri’s team will start by looking for differences in genes already known to be associated with epilepsy. But it’s likely they’ll end up sequencing the entire complement of protein-coding genes—whole-exome sequencing. That’s a step that wasn’t practically possible until recently.
“Once we find a gene, we can ask, ‘what is that change doing?’” says Poduri. “You can study the gene in animal models, and go back to large human populations to see if the mutation is important in other families.”
These genetic investigations may do more than solve a mystery for each family. With luck, and more research, they could lead to practical treatments. Epilepsy affects 1 percent of the population, and there are probably many roads to it. The more that are mapped, the more treatment options there are—not just for rare types of epilepsy, but common ones.
“We hope that one day a patient could be diagnosed and given a genetically informed profile that says, ‘here is the cause of your epilepsy, and here are the drugs that will work for you,’” says Poduri.
“When you have seizures, you treat the symptoms, not the cause,” says Gina Bergskaug, whose son Dante, now age 9, has been seizure-free for three years. “I’m hoping Dr. Poduri’s research will further enhance research on drugs that target specific causes of epilepsy. Now that she’s found something, people are doing research all over the world, and that’s what needs to happen.”
Learn more about the Epilepsy Genetics Program.