Genetic disease is ravaging Lancaster County's Amish, and helping to change medicine for all of us

STRASBURG -- Soon after birth, Daniel and Rebecca Stoltzfus's first child fell ill.

Fearing pneumonia, her parents rushed her to a hospital where she later died.

Testing revealed Severe Combined Immunodeficiency (SCID), a rare genetic disease, as the cause of death.

The condition, an inherited disorder of the immune system known colloquially as "the bubble boy disease," is present in roughly one in every 40,000 to 70,000 live births in the U.S., according to the National Institutes of Health.

But in the Stoltzfus home, the rate is one-in-four. "We have 12 children and three of them ended up having SCID," Daniel Stoltzfus said.

For the Stoltzfuses, their children and thousands of Amish like them, the odds are centuries in the making and rooted in something called the "founder effect."

It exists at the unlikely intersection of random chance and deliberate community planning: The result of generations of intermarriage, genetic drift and the biological bottleneck those factors have spawned.

In Lancaster County, where the Stoltzfuses live, the first Amish arrived from Switzerland between 1737 and 1767.

They sought to trade the religious schism in Europe at the time for Pennsylvania, William Penn's New Eden of planned tolerance.

And while the insular communities that followed allowed the religious sect to thrive and its practices to go largely unchanged for generations, they presented biological risks that only worsened over time as the population expanded but its genetic profile didn't.

Currently, more than 50,000 Lancaster County Amish can trace their lineage to just 80 ancestors, less than a tenth of what that number would be outside of the religious community in the 250 years, or 10 generations, since its founding.

Fewer ancestors mean more sharing of genetic material and any genetic defects -- the same linked to potentially fatal hereditary diseases like SCID -- contained therein.

Meanwhile, genetic defects not found in the settler population remain locally non-existent.

This is the founder effect, and evidence of it has been found in Amish and Mennonite populations from Pennsylvania and Ohio to Ontario, Canada.

In Lancaster County, the resulting rash of certain childhood diseases and birth defects drew the attention of a Philadelphia medical fellow who, tracing them to the Amish here, began a project that would alter the course of genomic science, medicine and this community forever.

He called it the Clinic for Special Children.

The human costs

Bunker Hill Road snakes along the low, marbled hills of Strasburg like a mule path.

It stretches between the outbuildings of large animal farms, and snaps like a bullwhip in the corners, where the edges of those farms force the road, and drivers, to go around.

At the end of a rutted dirt driveway jutting off to the south, the Clinic for Special Children -- a large, wood-framed building hidden behind the tree line -- has drawn a crowd for a planned community day.

Amish and Mennonite families, including the Stoltzfuses, are there, along with doctors and specialists in pediatric and genomic medicine.

The juxtaposition is startling: Old Order Amish mingling with the vanguards of modern medicine. Shunners of technology in a building brimming with some of the finest examples the 21^st century has to offer.

But here, the "men of science" and "men of God," share a history.

They share an icon, too.

His name is Dr. D. Holmes Morton.

Morton, a Harvard Medical School graduate, was working at the Children's Hospital of Philadelphia in the late 1980s when the first cases involving Amish children from nearby Lancaster County came through his door.

By all accounts Morton grew obsessed with explaining them and in 1989 he and his wife, Caroline, moved to Strasburg to be on the front lines. The clinic was opened soon thereafter.

Morton's first casework involved a group of 16 Amish children diagnosed with "Amish cerebral palsy," until then a fringe medical mystery with no known cause.

Morton determined all but one shared GA1 or Glutaric Aciduria, Type 1, an inherited metabolic disorder that leads to a build up of potentially harmful acids in the blood. Unchecked, it can prompt a metabolic stroke that leaves Amish children paralyzed or "locked-in" -- able to think and feel, but not to speak or move.

The condition is present in one in 400 Amish births in Lancaster County, and  almost non-existent outside of it.

Through the clinic's development of new diagnostic tools and treatments, as well as its groundbreaking use of genetic mapping, Morton was able to zero-out what was once a 93 percent injury rate.

He did the same with Maple Syrup Urine Disease, a recessive and potentially fatal metabolic disorder named for the sweetish odor it lends to bodily fluids like urine and earwax.

Before the clinic, the disease carried a 60 percent morbidity rate with local Mennonites -- 1 in 100 of whom are born with it, compared to 1 in 180,000 worldwide.

The clinic has since treated more than 110 Mennonite children and eliminated the death rate altogether.

Doctor Kevin Strauss, the clinic's medical director who took over for Morton in 2009, said to date, hospitalizations from the metabolic disorders studied and treated at the clinic have fallen by 96 percent.

"That alone," he said, "is a very compelling argument for the sort of human cost of not having services available like this."

'It's gonna hurt us'

As for the literal costs, Strauss estimates the clinic saves the local population on the order of $25 million a year in terms of reduced hospital and reduced morbidity rates.

The clinic takes no federal research funding and instead derives a third of its annual $3 million operating budget from the "Plain" sect communities it serves. Most of the money is raised through church fundraisers and community auctions.

"That's a 10-to-1 return rate," Strauss added.

Financial benefits like these cannot be overstated in a population in which almost no one is insured and in which many are exempt from Affordable Care Act mandates.

Leon and Linda Hoover, Mennonites from Mifflinburg, said they found themselves facing huge medical bills without insurance when their daughter Kendra was hospitalized with SCID-related complications soon after birth.

At 16 days old she received her first bone marrow transplant, the only known cure for SCID, in a procedure costing up to $800,000 in the first year, according to the National Foundation for Transplants.

It didn't take.

The second was performed at five-and-a-half months of age and Kendra remained in the hospital, under observation, for two months.

Through the clinic, the Hoovers were able to negotiate a 70 percent discount.

Without it, Leon Hoover, a clean-shaven and cheerful man in suspenders and khakis, said their church would have helped with fundraisers, adding, "It's gonna hurt us, but we don't do it alone."

Kendra, now 4, has grown into a happy and healthy child; and her parents say they are forever grateful to the clinic and its staff for helping her.

"It's part of our family here," Leon Hoover said. "They treat us like family."

'Make everyone healthier'

Morton's approach was unusual not just in its focus on providing low-cost care to a traditionally underserved segment of the population, but also in its reliance on a largely untested technology to do so.

When Morton first opened the clinic, genomic medicine and genetic testing were still in their infancy. But his interest in both, along with his background in the related field of biochemistry and hunch that genetics were the common thread linking childhood diseases in the Amish, all made him an early adopter.

Since its inception, the clinic has emerged as something of a proving ground in this arena, using genetic testing to find donors for patients like Kendra Hoover more readily; to detect diseases and prevent or delay the onset of symptoms; and to determine what treatments are most likely to be effective.

"What if we can pick up a child at birth and do a genetic test and say, 'Ah, this kid is carrying a variant'?" Dr. Erik Puffenberger, laboratory director at the clinic, mused. "And we know children (with that variant) start to have seizures by the time they are three years old. So the question becomes, 'What can we do for this child from birth to delay or prevent seizures?' That's where the work here is really important. In identifying the children when they're well, before the onset of symptoms, we can pick them up early and say, 'Is there any change we can affect?'"

To say applications like these will change the face of modern medicine is putting it mildly. And for some, it's less a matter of if, than when.

Before his death, Charles Epstein, a leading geneticist, wrote in the American Journal of Human Genetics: "There appears to be a pervasive belief in both scientific and public circles that genetic testing or profiling is going to be the cornerstone of much, if not all, of genomic medicine -- in fact, all of medicine -- in the future."

The theory has so far proven credible.

Genetics have already revolutionized cancer treatment and screening, making it easier to determine a person's chances of developing the disease before they do. Testing can also predict how a tumor will grow, which treatments will have fewer side effects and how likely cancer is to return after going into remission. One day, genetic testing may even help identify a dormant mental illness before it strikes.

But there are hurdles, as Epstein said, pointing to at times flawed predictions, questions about affordability, efficiency and how to properly train practitioners to interpret and apply findings.

"The danger is that these functions will become somewhat mindless operations driven by commercial testing companies and passed down to less qualified personnel," Epstein wrote.

He said this requires changing how doctors are paid, "if physicians are to be adequately reimbursed for the time that meaningful risk assessments and preventative interventions will require."

In short, it's still largely unclear what this new face of modern medicine will look like on a mass scale. Even more so because in many ways genomics runs counter to the health care infrastructure currently in place. To be fair, so did vaccines, antibiotics, birth control and transplants.

With genomics, it remains to be seen whether private companies will market the testing equipment or the testing itself. Whether patients will pay for their genetic sequence or just to have it interpreted. But given the growing interest from members of the public, private and health care sectors, it's unlikely that we'll have to wait long to find out.

At the Strasburg clinic, doctor Strauss acknowledged the dilemma this new frontier presents for profit-driven health care providers and the trillions spent on emergency and reactive health care in the U.S. annually. Regardless, he said, a future with genomic medicine is coming. And it is likely to be both irresistible and irreversible.

"Genomics can make everyone healthier," he said, before asking, "But will we have the humility and courage to take that lesson to heart?"

God's Will

Inside a clinic conference room, Daniel Stoltzfus and his wife were watching a presentation on blood diseases, part of the community day schedule of events.

Toddlers played at their feet. Others milled about the room. Some of them, probable bone marrow transplant recipients with hair missing from related chemo therapy and radiation treatments, moved more slowly than the others.

"It's very important to us. It helps us a lot," Daniel Stoltzfus said of the clinic, surveying the room. He added, "but it's changing a little. There are so many more people involved now."

What began as a novel experiment serving only a handful of patients has grown into an operation serving 1,200 currently, 90 percent of them Amish or Mennonite.

The numbers will likely continue to grow along with Amish and Plain populations across North America, expected to double every 20 years as more members stay within the church and continue to have large families.

For those that do, the risks of reproduction are widely known but largely unavoidable, Puffenberger said.

"You can't avoid marrying someone you're not at least distantly related to in these populations because of the small founder populations," he added.

"If you only have 80 ancestors you're going to have a lot of duplication (of genes), meaning you're going to be descended from those 80 founders probably multiple ways and so is anyone you marry."

But while intermarriage guarantees the continuation of bad genes, the doctor said a phenomenon known as genetic drift is responsible for their prevalence. The term refers to the random rate with which these genetic defects or mutations are passed on from parents to children.

Sometimes a mutation might be inherited by eight children in one family instead of the expected four, effectively doubling the likelihood of that mutation being passed on again.

Drift affects populations with fewer founders more significantly, meaning it's more problematic for Lancaster County's Amish, with just 80 founders, than the county's Mennonite community, with roughly 440 founders.

"The intermarriage part does amplify the problem but the biggest problem is the genetic drift which increases the frequency of the mutation in the population to the degree that you can have children born with this disorder even if their parents are eighth cousins," Puffenberger said.

The Amish know the odds, but have an unwavering belief in God's Will and the survival of the church, above all else. For those reasons, things are unlikely to change.

What has changed, though, is the way in which health care measures will influence those odds, and outcomes, for generations to come.

"What The Amish and Mennonite have allowed us to do is to glimpse into your future," Dr. Strauss told a Lancaster crowd in 2014.

"They have allowed us to glimpse the future of medical care and show us a way in which genomic knowledge will improve the well-being of people all over the world."