The unthinkable happened to Prudence and Jon Marsh. Twice.
The couple’s first child, Teagan, lived only two hours. She died before her parents could hold her. A fast-moving infection, the hospital staff said.
A year later, their son Jackson was born. His mother held him for only a minute before the staff hustled him into neonatal intensive care — merely as a precaution. He seemed perfectly healthy. Then Jackson began turning blue. Acid was building up in his blood and his tiny body couldn’t clear it. He lived just 13 hours.
As the Marshes, who live in Northern California, tried to recover, a team of researchers set out to determine what had killed their babies. They conducted lab tests. They grilled colleagues. One by one, they eliminated all the most common causes of newborn death.
At last, they turned to a genetic screening test that had recently become more affordable. This month they published their findings: A genetic mutation in a gene called lipoyltransferase 1, or LIPT1, had killed both babies.
And it may be more common than anyone had realized.
A memorial to two lost newborns
After they lost their first two babies, Prudence and Jon Marsh decided not to risk another pregnancy.
In the summer of 2010, the couple had become the guardians for a niece, who was then 7, and nephew, 12, who had been in foster care. After Jackson’s death, they put aside their dream of having their own children and focused all their energy on raising their niece and nephew. “We just figured those were our kids,” said Prudence.
But they couldn’t stop thinking of the babies they’d lost. It was a painful time.
“I refused to put up a Christmas tree. I hid out on birthdays and holidays. I avoided aisles in the grocery store,” Prudence said.
She and her husband set up a memorial in their living room to the children they lost.
A framed ultrasound of Teagan sits on the shelf, and a candle in the shape of the number 5. That’s how old she would be now, if she had lived. There’s a number 4 candle for Jackson, and a few picture books. A handful of plastic butterflies alight on photos of the babies.
As the years went by, the principal researchers into the deaths — a team at the University of California, Davis — kept the Marshes informed of their progress.
It was in early 2014, two years after Jackson’s death, that the team told Prudence and Jon they’d identified the lethal mutation with help from scientists at the University of California, Los Angeles.
A month later, Prudence realized she was pregnant again.
‘Statistics hadn’t been on our side’
Statistically, just 1 in 4 Marsh babies should inherit the recessive flaw that was in both Prudence’s and Jon’s genes. But two already had.
Could they bear another loss?
At the end of her first trimester, Prudence went in for tests. She was carrying a girl — a girl without the LIPT1 mutation.
Dr. Véronique Taché, a maternal and fetal medicine expert at UC Davis, said she was confident that LIPT1 was the culprit and that the Marshes’ third baby would be healthy.
It wasn’t just the genetic testing that gave her confidence: This pregnancy was different from Prudence’s previous two. The fetus moved around more and was heavier. “Those two things made us feel like yeah, this kiddo is probably going to be just fine,” Taché said.
“It was still scary,” Prudence said. Her doctors were telling her they were 99 percent sure the new baby would be fine. She didn’t share that certainty.
“Statistics hadn’t been on our side before,” she said.
Prudence waited until two weeks before her due date to get the baby things out of storage.
Taché vowed to oversee the delivery and wait in the hospital for a few hours to be sure that all went well. The Marshes insisted on keeping their baby with them this time. If she died, they needed her to be in their arms, not in an intensive care unit.
“They knew what they wanted,” Taché said. “That takes a lot of inner strength.”
For the third time, Prudence gave birth without a C-section or pain medication. Sadie was born pink and screaming, and weighing more than 9 pounds — 2 to 3 pounds heavier than her siblings.
As the hours passed, it became clear: She was healthy.
And because she didn’t inherit the LIPT1 mutation, Sadie can’t pass it on to her own children when the time comes.
An answer at last
The detective work that uncovered the flawed genetic code that killed Teagan and Jackson took effort. And also, luck.
Shortly before the researchers sent Jackson’s DNA for a genetic screen called whole exome sequencing, two papers had been published implicating LIPT1 mutations in the deaths of two other infants. Those babies were months older than the Marsh newborns, but both died from the same kind of acid buildup that had claimed Jackson.
When Jackson’s results came back, those case reports helped the research conclude with confidence that the LIPT1 mutation had caused his death. If those reports hadn’t recently come to light, they might not have been so certain.
More luck: After Jackson’s genetic analysis, the UC Davis team reached out to the coroner who had done Teagan’s autopsy to see if he could shed light on her death. He still had slides with her genetic material. And he was willing to send them to UCLA for analysis.
The results confirmed that Teagan had the same mutation.
Taché said she and the other experts working on the case were driven by their questions. Healthy American mothers just don’t lose two newborns for no reason. “I think all of us needed to figure it out,” she said.
Finding a genetic cause relieved Prudence and Jon of the guilt they had felt after both babies died.
“It wasn’t our fault. It wasn’t anything we did, or could have done, or should have done,” Prudence said. Finding the truth “was something that made it possible for us to even think about having kids again.”
Dancing with Sadie
Solving the mystery may also help others.
Taché thinks the LIPT1 mutation might not be that rare. Now that deaths in three families have linked the mutation to lethal acidosis in infants, doctors can begin to look for it in other cases.
“Hopefully it will clue in other physicians who are looking for reasons — why did this baby die?” she said. “I would like to see it incorporated in panel of tests for babies that have passed away.”
Taché also hopes that the Marshes’ story will motivate others facing medical mysteries. “It taught me a lot in terms of ‘Don’t give up, don’t despair, reach out to people at other universities,’” she said. “It only takes one person to be interested.”
The saga also showed the value of whole exome sequencing, which scans the 1 percent of the genome that is most likely to have dangerous mutations. It’s an extremely effective way to identify rare diseases, said Daniel MacArthur, a geneticist at the Broad Institute of MIT and Harvard.
Though each individual mutation may be rare, about 5 percent of Americans are believed to inherit one of these genetic errors.
Whole exome sequencing is becoming increasingly common as the price drops, MacArthur said. Researchers can get it done for about $600, though the cost is much higher for individual patients, and insurers generally won’t pay.
It’s also crucial, MacArthur said, that researchers, doctors and companies share what they learn about these rare mutations, he said, so other people can be helped by what’s been discovered.
Prudence said she hopes her experience will help someone else avoid the nightmare she endured: “They won’t have to go two kids and five years waiting for an answer.”
The Marshes named their third child Sadie Bee, because it made them happy to say.
And Sadie Bee is a happy little girl.
These days, the family gathers in the living room, rather than hiding out in their own rooms with their grief. Sadie, now 17 months, has learned to turn on the radio.
“Sadie will start dancing and we all will crack up and get goofy with her,” Prudence said. “She knows she can get a good smile out of anyone at any time.”