An Advocate for the Amish at a Very Special Clinic

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400px-Amish_country_2Last Wednesday, I finally met Dr. D. Holmes Morton, a pediatrician who is quietly conquering genetic disease among the Amish and Mennonites – on their own turf, at the nonprofit Clinic for Special Children in Strasburg, PA.

I’d written about Dr. Morton in my human genetics textbook circa 2000: “In 1989, D. Holmes Morton, a research fellow at Children’s Hospital of Philadelphia, discovered that several young children from Lancaster County with cerebral palsy presumably caused by oxygen deprivation at birth instead had an inborn error of metabolism called glutaric aciduria type 1. Morton went from farm to farm, tracking cases against genealogical records, and found that every family that could trace its roots back to the founders had the disease!”

familyA CURIOUS CASE OF CEREBRAL PALSY LEADS TO OTHERS
The story began at the Philadelphia children’s hospital late one night in spring 1989, when Dr. Morton found glutaric acid, the hallmark of the extremely rare inherited disease (GA1), in a urine sample from a boy who had what looked like cerebral palsy. But the medical history was puzzling: 6-year-old Danny Lapp, who came from an Amish family, had been healthy until soon after his first birthday. After a stomach bug, the boy had suddenly become unable to move or speak. Such severe brain damage typically is obvious at birth.

Because the medical literature reported only a handful of cases, calling the disease aciduria (in the urine) or acidemia (in the blood), Dr. Morton decided to drive the hour to Lancaster county to visit the family. The curious pediatrician knew about the higher frequency of certain genetic diseases among the Amish and the Mennonites. Would he find other cases?

The genetic diseases that are more prevalent among the “Plain” people are not unique to them, but are the consequence of taking a small sample from the European gene pool from which they came. The Amish and Mennonites, and several other groups, vividly illustrate genetic drift – a non-representative sample of gene variants (alleles) from a genetically diverse population is amplified when a few individuals leave to start a new settlement, marry among themselves, and have large families. Sometimes such migrations come in waves, with communities popping up over a widespread area, such as the continental U.S. And sometimes the selected genes are amplified further through population bottlenecks, when numbers drop.

A diverse handful of jellybeans mimics and ancestral, genetically diverse human population.

A diverse handful of jellybeans mimics an ancestral, genetically diverse human population.

A collection of jellybeans can be used to illustrate the dwindling genetic diversity of genetic drift. Start with a scoopful of jellybeans of dozens of colors. Then select and set aside eight. Imagine the original collection and the group of 8 replenish themselves, separately. After awhile, remove pairs of jellybeans, one at a time, from each collection. The chance of removing two identically-colored jellybeans – representing recessive mutant alleles for the same gene — is considerably greater from the jar of eight types than from the jar of dozens. That is the chance sampling of genetic drift. When the situation arises from a small group leaving a larger ancestral one, genetic drift is called a founder effect.

Selecting a few jellybean colors mimics a founder effect.

Selecting a few jellybean colors mimics a founder effect.

At least a quarter of the so-called Amish mutations aren’t unique to the Amish at all, but came from and remain in Europe. “Most of the human genetic diseases in Europe were replicated in pockets, as the subpopulations that we study,” Dr. Morton explained as we drove to the clinic from the train station last week. “People think that maple syrup urine disease is only in Mennonites and GA1 in the Amish only, but no, they are European mutations sampled in migrations and then clustered due to a founder effect. The idea that the population is inbred and that caused the genetic disease is not quite true.”

Back at the beginning, Dr. Morton asked the Lapps if they knew anyone else who had symptoms like Danny’s. They did. A neighboring family had lost two of seven children to the strange illness, and three others were severely brain-damaged. All told, 26 young people in Lancaster had the late-onset cerebral palsy. They’d either been misdiagnosed or not diagnosed at all, and that was the biggest problem: physicians didn’t recognize these incredibly rare diseases. To get specialized care, the Plain people had to make long journeys to urban medical centers. And often even there no one could provide an answer.

GA1 didn’t stand a chance against Dr. Morton and his colleagues. They described the Amish cases in a paper in 1991, identified the gene in 1996, and in 2011 introduced the dietary treatment they invented that balances two types of amino acids to counteract the metabolic glitch of the disease. Today, youngsters diagnosed following newborn screening can grow up healthy. (More about the “medical food” in another post.)

farmA CLINIC IN THE MIDDLE OF A CORNFIELD
In 1989, with funding that flowed in after Wall Street Journal writer Frank Allen published a moving article about Dr. Morton’s efforts, the beautiful post-and-beam building arose in a cornfield that was part of the Stoltzfus family farm. A single Stoltzfus was one of the original founders of the community, and today the family makes up 20% of the local Amish population. Some of the grandchildren have genetic diseases.

As the building went up, the people’s skepticism went down. “That was a watershed event. Then the community bought in. The summer after we moved in, the community held its first benefit auction,” Dr. Morton said. And the locals have been fundraising ever since.

Dr. Morton and Kevin Strauss, MD, a pediatrician and Erik Puffenberger, PhD, a geneticist, described their facility in the American Journal of Public Health (“One Community’s Effort to Control Genetic Disease”): “Our Clinic for Special Children was established … to incorporate subspecialty knowledge of population genetics, molecular biology, and the technologies these entail into a rural pediatric clinic serving uninsured Amish and Mennonite (Plain) children with genetic disease.”  The goal: to diagnose genetic diseases early enough to intervene. And that has increasingly meant inventing the interventions.

Today, the clinic sees 2,300 people with 140 recessive disorders, including about 500 adults. About half of the conditions can be treated, at least in patients diagnosed before the disease progresses too far. Most patients are from surrounding parts of the state, but they come from 33 other states and 14 countries. Each family has one or two recessive mutations – some conditions have carrier rates as high as 1 in 10. And now that the clinic has brought in a third pediatrician, Katie B. Williams, Dr. Morton is looking beyond the former cornfield, trying to convince other communities to set up clinics to identify genetic diseases early enough to treat.

MEETING DR. MORTON
I kept the short descriptions of Dr. Morton’s early work in the seven subsequent editions of my textbook. Lisa Belkin wrote about the clinic for The New York Times in 2005. But it was shortly after Trisha Gura wrote about it in Nature that Jonathon Coren, who teaches at Elizabethtown College, one Amtrak stop beyond Lancaster, invited me to lecture in his genetics class in November. He talked enthusiastically about the clinic, and how he’d have to get me together with its director. He tried to schedule my talk at the college right after Dr. Morton’s, so we could meet. I still didn’t realize he was talking about the man I’d been writing about in my textbook.

Alas our visits to the college in the fall didn’t quite overlap. So I was thrilled when Dr. Morton invited me to attend a 2-day conference at the clinic, called Genomic Medicine and the Plain Populations of North America, last July. As I read more about the clinic, I finally realized who Dr. Morton was. But I missed the conference, at the last minute, due to a family emergency, and it seemed I’d never get to meet the man who was systematically taking on the rare genetic diseases of the Amish and Mennonites. But then I was asked to speak at a college in Philadelphia on December 2, and at Penn State on December 5. The Clinic for Special Children was right in the middle!

Amish kids get to school on these "scooters."

Amish kids get to school on these “scooters.”

So on December 4, Dr. Morton picked me up at the train station. Lancaster, full of art galleries and music centers, didn’t match my childhood memories. Minutes later, we were in Amish country. On the left we passed a one-room schoolhouse with small bikes in front. To the right as the road snaked through fields peppered with cows and chickens was a silo and farmhouse in the distance. “That was the set for the film Witness,” Dr. Morton said.

We soon pulled up at the Clinic, a post-and-beam timber dwelling that looks more like a country getaway than a place where downstairs families gather and upstairs their exomes are analyzed. As we stepped onto the porch, I noticed the sound – a constant clacking of crows interrupted with the honks of geese. After Philadelphia, it was nice to leave my stuff in an unlocked car without a worry.

The sense of straddling two worlds was palpable as I entered the modest building held together with pegs, and office manager Rebecca Smoker, clad in traditional Old Order Amish dress, waved hello as she spoke Pennsylvania Dutch into her cell phone. She’s the aunt of the kids with GA1 who live near the Lapps. Danny, the original patient, died a few years after Dr. Morton first analyzed the boy’s urine sample.

When the clinic opened in 1989, Dr. Morton, his wife Caroline as executive director, and Rebecca were the entire staff. “In the early days, before the molecular work, we used Rebecca and her genealogies. She’d figure out who to give carrier tests for GA1 to.” The farmers and midwives familiar with the disease helped too.

We stopped at the small but packed lab where high performance liquid chromatography and mass spectrometry are used to measure the concentrations of various organic acids in blood samples, indicating carriers and diagnosing the affected. Tests that once took days because samples had to be sent out can now be done in under two hours. And the lab tests that indicate phenotype are complemented by targeted molecular diagnostics to identify mutations that nail the genotype.

Because the clinic’s patients would not end pregnancies, prenatal diagnosis isn’t typically done — but midwives collect amniotic fluid once a woman’s water breaks, and send urine samples from diapers. The earlier the diagnosis, the more likely a child can grow up without the disease encoded in his or her genes.

Amish_-_On_the_way_to_school_by_Gadjoboy-cropI was a little disappointed that there would be no patient visits that day, but as we walked down the short hallway outside the lab, I saw a family settling into a playroom at the end. We passed some of Dr. Morton’s daughter Sarah’s remarkable portraits of Amish life along the white walls that stretch between the wooden beams. On one canvas across from the entranceway, a cow’s face emerged to a focal point from blurred images in the periphery, a style repeated in the other glimpses of the Plain way of life from the artist who grew up alongside the people she captures in her portraits.

The family in the playroom was in full Amish attire. The couple were in their thirties or perhaps early forties, the man’s beard well below his chin. A pre-teen girl sat on a sofa, with a lopsided grin, and the mother held a beautiful, chubby baby who was pulling at her bonnet strings.

This photo from 1941 shows the characteristic haircut of Amish men and boys.

This photo from 1941 shows the characteristic haircut of Amish men and boys.

Zooming about the toy-littered room was a boy with a bright smile and dancing eyes who came right over and reached for my hands. His shining light brown hair was bowl-cut. He looked a bit like Pete Townshend in the old days of the Who, but with a button rather than a beak for a nose. I instinctively hugged the charming little boy, and fortunately the thinking part of my brain turned itself on and I slipped my iPhone, camera ready to go, back into my pocket.

The family was very happy to see the doctor, and the father, concerned, spoke right up. “His seizures are hard to control. He has them in the morning and then around dinnertime. The medicine doesn’t seem to last long enough to keep them at bay,” he told Dr. Morton. They’d adjust the meds, the doctor answered.

As we left, Dr. Morton explained that visiting the clinic twice a year is a hardship for the family. “They travel 300 miles from the other end of the state, paying a driver a dollar per mile.” The Amish do not have health insurance and do not take government aid – instead they work and raise funds to support each other.

The family has six children and five of them inherited a seizure/autism disorder due to a mutation in a gene called CNTNAP2. With both parents carriers, each child faced a 1 in 4 chance of inheriting the condition. Multiplying 1/4 by five gives a probability of 1 in 1,024 that five of the six kids would have it. The family is genetically unlucky.

But they’re lucky in that their disease is one of the success stories in which early diagnosis and recently-developed intervention help – that’s why the oldest are the sickest. It’s a familiar theme in the inborn errors of metabolism arena, begun with PKU, in which restricted diets or medical foods can prevent intellectual and physical disabilities. If a medical food becomes available after some of the siblings are a few years old and the damage done, the family becomes an experiment – the older kids are far sicker than the younger ones who’ve been treated.

I pulled myself away from the happy boy to follow Dr. Morton downstairs, to a room where, three times a week, the Special Hearts Club meets. That day, the club was in full swing, and I was astonished. Tune in next week.

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4 Responses to An Advocate for the Amish at a Very Special Clinic

  1. Jon Coren says:

    Ricki,

    You have brilliantly captured the ethos of the Clinic for Special Children! Your writing style and analogies bring human genetics to life for the layperson. I can’t wait to read your next post.

    Jon

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    • Ricki Lewis says:

      And I want to drop all my other work and go back there and help out, and write more. Thank you! You made this possible.

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