In 2004, Dr. Michael Ackerman got an unexpected phone call.
On the other end of the line was a medical examiner in Kentucky who had recently performed a befuddling autopsy on a 12-year-old Amish girl.
“He was perplexed why this seemingly healthy Amish child died suddenly during play,” said Ackerman, a genetic cardiologist at Mayo Clinic who studies why some young people die unexpectedly. “And he says, ‘I have DNA for you.’”
Ackerman, who also leads Mayo’s Windland Smith Rice Sudden Death Genomics Laboratory, pioneered a postmortem test to detect genetic causes behind sudden death. The medical examiner in Kentucky had heard about his work.
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That phone call would ignite more than a decade of genetic sleuthing across multiple states to understand why a healthy Amish child had died without an obvious explanation. The mystery of her death — and later, the deaths of more than a dozen other Amish children — would vex researchers and clinicians for years, until Ackerman and his colleagues finally made a breakthrough in their Mayo lab.
Those findings were recently published in the JAMA Cardiology medical journal. Now, those same researchers are working to find a treatment.
‘We just needed the technology to catch up’
Not long after the medical examiner’s call in 2004, Ackerman and his team were just beginning their research into the girl’s DNA when tragedy struck again. Four months after losing their daughter, the family lost her 10-year-old sister under similar circumstances — suddenly, while she was outside playing.
Ackerman said his research team had a hunch the siblings’ deaths involved a gene called RYR2. When there's a single error on the gene, it causes an irregular heart rhythm that often reveals itself in the form of fainting spells while exercising. It can be fatal.
But that was more than 15 years ago, and medical research tools hadn’t quite caught up to the team’s needs.
“Back then, it was painfully slow. It sort of was one gene at a time,” Ackerman said.
After extensive testing of the girls' DNA, the Mayo researchers still had no answers.
“We basically had a project that was stalled and would stay stalled until we would have evolution of technology,” Ackerman said.
Over the next decade, 16 more Amish children died while exercising, without warning. The same family that lost their daughters in 2004 lost two more children under similar circumstances. Amish children in other states died, too.
While Mayo’s research languished, more than a thousand miles away, doctors at the Nemours/Alfred I. duPont Hospital for Children in Wilmington, Del., encountered a similarly tragic story.
In 2005, a young, apparently healthy Amish child was playing and died suddenly. The autopsy revealed no obvious cause. Several years later, the girl’s sister experienced cardiac arrest but survived — and she is still living, 15 years later.
“This started a trend, essentially, in their family,” said Kristi Fitzgerald, a genetic counselor at Nemours and an author of the JAMA paper. “It’s not just a fluke chance, a terrible, tragic event. Now with two girls in one family, the presumption was that this probably was a genetic cause, something to do with a genetic arrhythmia.”
But just as in Ackerman’s lab in Rochester, Minn., genetic testing at Nemours turned up nothing.
Over the years, Nemours staff collaborated with Mayo staff, and in the process learned that the sisters who had died in Kentucky were from the same extended family as the child who had died in Delaware.
Researchers also identified additional relatives in Iowa who have the same genetic defect. To date, no members of Amish communities in Minnesota appear to have the condition.
Clinicians at Mayo and elsewhere are fiercely protective of the families affected, and declined to identify them to maintain their privacy.
In Rochester, Ackerman and his staff continued to collect DNA samples from the children who died in this perplexing way, hoping someday to figure out the cause of their death.
They just needed the technology to catch up. In 2016, it started to.
Ackerman said new testing techniques revealed that the sudden deaths weren't caused by just one error on the RYR2 gene — they were caused by 300,000 of them.
What's more, the risk of sudden death came only when the children inherited that faulty gene from both parents.
"We basically did genomic triangulation and figured that all of these sudden deaths and all of these different Amish communities were happening for the exact same reason: a double whammy, a double hit of this exact same duplication,” Ackerman said.
Genes traced back to founder individuals
Nemours pediatrician Matthew Demczko has made a career working with Amish children who live with an array of genetic abnormalities.
He said the genetic heart defect detected by the Mayo team is likely unique to the Amish community. That’s because researchers think people with the defect are all connected to a small number of people who established a particular Amish community from which the children affected were all descended. Those people are what Demczko calls "founder individuals."
“Their genetic information has now become sort of the genetic thumbprint of the entire community,” he said.
Demczko said Amish communities tend to be small and insular, and members of the community typically marry and have children with people who are also Amish.
“That factor on top of the idea that from a cultural perspective, very few individuals come into the Amish community, there's really no introduction of new genetic material,” he said.
Fitzgerald, Demczko’s colleague, is on the front lines of screening members of Amish communities in their region for the defect. She said that Nemours’ positive reputation in nearby Amish communities helps in her work.
“Word of mouth is important,” she said. “I think that's a great source of referral, to have a patient to say, ‘We had a good experience. This went well.’”
Fitzgerald said her Amish patients ask the same questions about genetic testing as other families do: What will the test tell them? Why is the test important? What will they do with the information if they test positive?
And she said it's a misconception that Amish people shun medicine.
The families she’s worked with, she said, have been open to testing and treatment.
"Parents want what's best for their child. It's about building a relationship, you know, with the family,” she said. “Most are not at all skeptical."
Fitzgerald said that some parents whose children have tested positive for the condition have opted to get an implantable defibrillator, which is the only available treatment.
But many Amish families don’t carry health insurance, so that solution is not only invasive, but can be prohibitively expensive.
Finding the cause, searching for a treatment
Back at Mayo, researcher Dave Tester is trying to better understand the genetic defect he helped discover. Now that they’ve pinpointed the cause of the children’s sudden death, they’re trying to find a more affordable and accessible treatment.
"This is sort of phase 2 in this study,” said Tester, who also authored the JAMA article.
To do that, the researchers turned to another novel approach: They engineered beating heart cells from blood samples donated by two people living with the condition.
He points to a cluster of heart cells undulating rhythmically under a microscope.
"These cells have the same exact genetic background that our patient does,” he said. “Here we can understand, at least from this patient's perspective — what is the cell doing?"
In the coming months, Tester and his staff will perform a battery of tests on these cells, looking for clues that point them toward a better treatment.
But in the meantime, Mayo and Nemours continue to collaborate to understand just how common the condition is and how widespread. Their network has also extended to Iowa, where a genetic counselor is working with nearby Amish communities.
To ease that process, Mayo has made the test free for Amish families who may be affected.
Fitzgerald, the genetic counselor, is hopeful additional screening in Delaware and in other Amish communities will reveal more information about the condition.
And while she may not be able to offer her families a perfect solution today, at least they're starting to get some answers.
“We don't want to give false hope, but I think it is important to tell families how far we come,” she said. “We tell people ‘Hold on, stay tuned.’”