#How a global epilepsy initiative is helping to heal children

Levi Trowbridge was just 3 days old and newly released from the maternity ward when he went into convulsions last year.

Karsha Trowbridge — a first-time mom — said she and her husband, Steve Trowbridge, were “shocked and confused” by their newborn’s unusual behavior.

“We had just got home and as far as we knew, he was a perfect, healthy baby,” she said.

“We thought he may have just struggled to bring up wind at the start.”

But when the family was visited the next day by a maternal-health nurse provided by the state of Victoria in their native Australia, Levi was again racked by a seizure.

At the nurse’s direction, his parents rushed him to the nearby Northern Hospital Epping, “where he had another four that day,” said his mom, a 29-year-old child-care worker.

Despite being treated with multiple anti-seizure drugs, Levi didn’t get better.

“It was a terrifying time, watching your baby have multiple seizures a day and, at times, turning blue and holding his breath,” Karsha said.

Within a week, Levi was transferred to the Royal Children’s Hospital in Melbourne and put under the care of Dr. Katherine Howell, a pediatric neurologist and the epilepsy team leader at the Murdoch Children’s Research Institute.

The charitable organization was co-founded by the late Dame Elisabeth Murdoch, the philanthropic mother of Rupert Murdoch, the founder and executive chairman of News Corp and chairman of The Post.

Although Levi’s initial diagnosis was early infantile epileptic encephalopathy, he had other worrisome symptoms, in addition to his frequent seizures, Howell said.

“He was floppy and lethargic and, for a time, needed support with his breathing and feeding,” she said.

Howell arranged “ultrarapid” genomic testing of Levi through a study of critically ill children led by the MCRI’s not-for-profit subsidiary, the Victoria Clinical Genetics Service.

“Levi was recruited to that study and we had a result five days later,” she said.

The testing uncovered a very rare condition known as KCNQ2 encephalopathy, which is linked to a mutation in the gene that regulates potassium in the brain.

Armed with that information, Howell treated Levi with oxcarbazepine, an anticonvulsant medication, and weaned him off the other drugs that weren’t working.

“Levi improved rapidly — his multiple daily seizures stopped by the time he was 3 weeks old,” Howell said.

“He was more alert, started to feed well and was able to go home from the hospital.”

Little more than a year later, medical experts around the world now hope to learn from Levi’s experience — and those of other babies — to improve treatment for infants with epilepsy.

A new project — the International Precision Child Health Partnership, or IPCHiP — will see four major pediatric centers on three continents join forces to analyze medical and genomic data to speed up the development of new therapy regimens.

In addition to the Murdoch Children’s Research Institute, the Royal Children’s Hospital and the University of Melbourne, the participants are the Boston Children’s Hospital, the Hospital for Sick Children in Toronto and the UCL Great Ormond Street Institute for Child Health and the Great Ormond Street Hospital in London.

The plan — revealed here ahead of Sunday’s international observance of Rare Disease Day — has been in the works since 2019, said Professor Kathryn North, director of the MCRI.

IPCHiP’s initial effort will focus on 100 babies diagnosed with epilepsy before they turn 1.

After sequencing their genomes and treating them accordingly, the children will be tracked and their outcomes compared with those of others for whom no genetic diagnosis can be made.

If successful, the project will eventually expand into a five-year study of 600 kids.

“This will represent the largest prospectively recruited early-onset epilepsy cohort for genetic study to date,” North said.

The program “is also unique in that it will gather prospective clinical and developmental data, unlike previous, large-cohort sequencing studies,” she added.

“This will allow the investigation of the impact and clinical utility of a precise genetic diagnosis in this patient group.”

The project’s goals include providing individual test results in less than two weeks, thereby enabling “real-time” treatment decisions with increased rates of success.

With epilepsy, quick action is especially important because it can minimize brain damage and “improve outcomes for these critically ill children and their families,” North said.

The MCRI was initially established as the Murdoch Institute by the late Professor David Danks, a pediatrician who in 1962 was encouraged by Elisabeth Murdoch to travel to the United States to study under the late Dr. Victor McKusick of Johns Hopkins University.

McKusick is widely considered the founding father of medical genetics, having launched the first medical-genetics program and clinic at Johns Hopkins in 1957.

After returning to Australia in 1964, Danks started that country’s first genetics unit at the Royal Children’s Hospital, and in 1993, he was part of the research team that discovered the genetic cause of Menkes syndrome.

The disorder, which affects infants and children, causes copper to build up in the intestines and kidneys but starves the brain and other tissues of that vital chemical element, leading to stunted growth and developmental disabilities that often cause death by age 3.

Elisabeth Murdoch — who co-founded the MCRI with Danks in 1986 — was a longtime benefactor of the Royal Children’s Hospital whose interest in helping sick kids dated to when she was 16 and knitted a record number of baby singlets for its patients.

“When I was young, conditions like polio and smallpox were the big health issues,” she said before her death in 2012 at age 103.

“Now you hardly hear of them thanks to tremendous advances in medical research.”

In the years since its founding, the MCRI has grown into an AU$172 million-a-year operation, with more than 1,300 staffers and nearly AU$18 million in charitable contributions, according to its 2019 annual report.

The Murdoch family has also continued its involvement, with Rupert Murdoch’s eldest son, News Corp. co-chairman Lachlan Murdoch, and his wife, Sarah Murdoch, last year funding an AU$5 million endowment to pursue “blue-sky research” into precision genomic medicine and new stem-cell technology.

North — who has headed the MCRI since 2013 — said plans are already in the works for a second IPCHiP project.

It would involve complex cases involving critically ill kids in neonatal and pediatric intensive-care units, particularly those “who have unexplained severe muscle weakness, which can be caused by a broad range of genetic disorders,” she said.

Rapid diagnoses of such ailments are critical, she added, because targeted therapies “can be transformative to the baby’s health” if implemented before the disease progresses.

North — who in 2019 was awarded the Companion of the Order of Australia, the country’s highest civilian honor, for her “eminent service to genomic medicine” — said recent advances in the field were “rapidly transforming health care” for children with rare syndromes that often go undiagnosed.

“In the past, we could give families with affected children a clinical description – a label – but we couldn’t pinpoint the cause or define exactly what was wrong,” she said.

“Now we are obtaining answers for 40 to 50 percent of children in a clinically important time frame and, equally importantly, we are in a much better position to tailor therapy very precisely, giving the right medicine to the right child at the right time.”

In Levi’s case, getting his test results in a matter of days, instead of months, made all the difference, Dr. Howell said.

“The rapid testing Levi had provides a glimpse of the potential benefits of rapid testing and diagnosis,” she said.

“We hope that our study of rapid genomic testing in early-onset epilepsies will show that it allows us to treat infants more precisely and improve their seizure and developmental outcomes.”

Meanwhile, Levi — who celebrated his first birthday on Jan. 14 — has been seizure-free since two episodes when he was 6 weeks old, Howell said.

“Levi has some developmental delays but is making solid forward progress,” she said.

“He can sit, he picks up toys, he can babble, he’s very interested in his surroundings and just lights up when he sees his parents’ faces.”

Howell added, “We don’t know for sure that Levi’s development is better than it would have been if seizures were ongoing, but he has had — and I expect will continue to have — a much milder course than I initially predicted.”

Levi’s mom said that neither she nor her husband has a family history of epilepsy and that their own genetic testing showed that Levi didn’t inherit his condition.

Karsha also said she and Steve understand that KCNQ2 encephalopathy is “a lifelong prognosis,” adding, “We are concentrating on seizure management whilst also scaffolding lifelong skills with professional help with any developmental delay that may arise.

“Levi is a happy and healthy boy who is a resilient and willing learner, reaching his milestones one step at a time with the assistance of occupational therapy and physiotherapy on a regular basis.”