The first clue that Dawn Sensenig’s fifth pregnancy was different from the rest was her enormous belly.
Carrying so large in her last trimester that she measured 10 weeks ahead of her due date, Sensenig’s internal alarm blared when her brother’s wife mentioned she had carried similarly while expecting a daughter who died at age 4 of a mysterious disorder in 2002.
But unlike her sister-in-law — and partly because of her relative’s tragic experience — Sensenig knew before she delivered in March 2012 that her baby might have a rare genetic disorder known as Pretzel syndrome. In 2005, in a modest, country-style clinic only 13 miles away from her Mennonite family’s 150-acre farm in Lancaster County, Pennsylvania, geneticists had discovered the molecular underpinnings of the disease, so-named because those afflicted have joints and ligaments so loose they can bend like pretzels.
By the time Jessica Sensenig was diagnosed with the syndrome at the Clinic for Special Children (CSC) at 2 weeks old — testing positive for a mutation of the LYK5/STRADA gene — Dawn and her husband, Cleason, also knew a lot more. Jessica, the only one affected of their now six children, would suffer from stubborn seizures and would never be able to function normally. She would likely never walk or talk, the Sensenigs were told.
And yet, critical advances in the understanding of Pretzel syndrome, or polyhydramnios, megalencephaly and symptomatic epilepsy syndrome (PMSE), meant Jessica wasn’t necessarily destined for the same dismal fate as her cousin. Collaborating with other researchers, notably Peter Crino, now of Temple University in Philadelphia, the CSC staff had determined that the immune system inhibitor Rapamycin (sirolimus) could quell the brain-ravaging seizures — considered the syndrome’s worst feature — and improve Jessica’s ability to understand others. She would be able to happily interact with her family.
“It was very overwhelming to hear the diagnosis,” recalls Dawn Sensenig, 33, clothed in a long, homespun dress and white bonnet. On a regimen of Rapamycin and the anticonvulsant drug Trileptal (oxcarbazepine) since infancy, Jessica hasn’t suffered a seizure in nearly two years.
“They told us these children respond well and that they’re social, and we’ve found that to be so true of Jessica,” adds her mother. “She’s been such a delight. If I’d known what I know now, I wouldn’t have cried for so long.”
Clinic’s Mission Fueled By Void in Care
Nestled against a cornfield in Strasburg, Pennsylvania, the CSC was the brainchild of D. Holmes Morton, an oft-bow-tied pediatrician, who followed his heart and instincts when deciding to diagnose and treat diseases disproportionately affecting nearby Amish and Mennonite populations.
Morton co-founded the clinic with his wife, Caroline, in 1989, and garnered the unwavering support of the so-called Plain people it serves. The CSC is deceptively simple, inside and out. The original timber frame was raised in 1990 in a single day by volunteers, who tirelessly generate about 60 percent of the facility’s annual $2.5 million budget through community donations, including old-fashioned auctions raising hundreds of thousands of dollars.
Working in a Philadelphia hospital lab in June 1988, Morton stumbled upon his life’s mission when analyzing the urine of a 6-year-old Amish boy diagnosed with cerebral palsy who had seemed completely healthy for more than a year after his birth. The urinalysis showed the boy actually had glutaric aciduria type 1, or GA1, an inherited metabolic disorder, which can be triggered or exacerbated by an infection. GA1 patients have low levels of an enzyme to process certain proteins, allowing toxic amounts of glutaric acid to build up and irreversibly damage the brain.
In Mennonites, Morton knew, maple syrup urine disease (MSUD) was a comparable scourge. (GA1 and MSUD affect an estimated 1 in 300 and 1 in 400 Amish and Mennonite infants, respectively.) Drawing its name from the sickly sweet smell of affected children’s urine, MSUD leaves sufferers unable to properly break down certain amino acids, leading to seizures, coma, and death if untreated.
Morton noticed how the families of these patients, all children of uninsured farmers and craftsmen in the Plain communities, crisscrossed the state in search of effective care — a time-consuming and seemingly impossible quest, because the large academic centers they visited rarely encountered cases like theirs. Meanwhile, brain damage in these children continued unabated. Morton was frustrated enough to cobble together a new clinic — and a new way of approaching these diseases.
“For a lot of these children and their families, the healthcare system was not only irrational, it was dysfunctional,” recalls Morton, in a twang that reveals his West Virginia upbringing. “By that time I knew that unless we found these children when they were healthy, before their brain was damaged, we’d never learn to treat the disease.”
Contained Populations Create Genetic Vulnerability
The Amish and Mennonites are alike in that their religious beliefs separate them from mainstream society, prompting them to dress simply and selectively shun modern comforts ranging from electricity to cars to Internet access. They also share a genetic vulnerability because they descend from small, contained groups of Europeans who immigrated to the United States in the 1700s.
Since the two groups — genetically distinct from each other — still live in relative physical and cultural isolation, marrying among their own, “present-day members can’t help but be related back to the same founders,” notes Adam Heaps, a laboratory scientist and administrative director at the CSC, which has grown to 16 staff members.
Lacking opportunities to figuratively shuffle their genetic decks, the Amish and Mennonites are disproportionately affected with certain disorders, particularly those caused by single-gene mutations. Dawn and Cleason Sensenig, for instance, unwittingly each carried one copy of a mutation in a gene that causes PMSE. Carriers like the Sensenigs are unaffected by the disease, which requires both copies of the gene to contain a damaging mutation. But, like 4 percent of Old Order Mennonites in Pennsylvania, Ohio, and New York who are also carriers, the Sensenigs’ children had a 1 in 4 risk of inheriting both defective copies of their parents’ genes.
The list of some 150 genetic disorders affecting Amish and Mennonites is dominated by those influencing brain growth and development and previously misdiagnosed as conditions such as cerebral palsy, autism, and epilepsy. Immune system disorders and those causing prolonged seizures, sudden infant death syndrome, lethal heart irregularities, and cerebral hemorrhages also appear.
Although the clinic’s researchers identify a handful of previously unheard-of disorders in these groups every year — having discovered, either alone or in collaboration with others, more than a quarter of the disorders on the list — these conditions are not unique to Amish and Mennonites. They merely appear more often because of the groups’ genetic vulnerability. In fact, these disorders occur in populations of people of European descent around the world. CSC tracks more than 2,700 patients in total, from more than 30 other states and 17 countries.
Treatments Improve and Save Lives
One floor beneath a cluster of sparely furnished patient exam rooms, the clinic’s basement genetics lab houses costly equipment yielding some of the most sophisticated DNA analyses done in the world. With the donation of a gene sequencer, staff members are able to offer quick, accurate results, sometimes in hours.
Rapid diagnoses have enabled Morton, fellow pediatricians Kevin Strauss and Katie Williams, and geneticist Erik Puffenberger to brainstorm interventions early enough to prevent some of the worst effects of these genetic illnesses or save their patients’ lives. In several cases, the team’s assessment has even spared Amish or Mennonite parents from criminal culpability when their children die suddenly or unexpectedly or show symptoms of puzzling illnesses that are mistaken for child abuse or neglect.
And some of these treatments have proven to be remarkably inexpensive and easy.
“One of the real values of this place is we have a kind of institutional memory that… allows us to have insight into these diseases that very few places have,” Morton says. “It’s a good example of chance favoring the prepared mind.”
By devising and refining medical diets that cut out foods and substances patients can’t metabolize because of their genetic conditions, and carefully monitoring their blood, Morton and his team have transformed young GA1 and MSUD patients into children virtually indistinguishable from their healthy peers. This outcome is possible, in part, because of a network of local midwives who collect blood samples from the umbilical cords of Plain community babies just after birth, which the CSC immediately analyzes. It uses the results to avert disaster among affected infants.
The facility’s rigorous screening of newborns for metabolic diseases spurred the state of Pennsylvania and others to follow suit. Before the CSC’s founding, half of GA1 children died, and most of the rest became profoundly disabled, Heaps notes; now, none suffers brain damage. Meanwhile, no MSUD patients treated at the CSC since 1990 have died and none suffers from cerebral palsy–like disabilities.
A quarter of a century ago, “We got endless criticism for testing for a disease we couldn’t treat,” Morton says of GA1. “Now it’s the standard of care in the U.S. It’s now known not to be a rare disease, and it’s considered very treatable.”
Clinic’s Impact Measured in HOPE
Jessica Sensenig will remain disabled for the rest of her life, regardless of the strides made in understanding Pretzel syndrome. But the value of the clinic’s insight, nonexistent even 10 years ago, is indelibly written across her mother’s steely, smiling face. The blond-haired girl, who chortles and babbles “hi” as a younger toddler might, has likely avoided a bleaker outcome because of her drug regimen, along with periodic blood tests and vision, heart, and joint checks. She also receives regular physical, occupational, and speech therapy in the family’s home.
“When I think about my niece … Pretzel syndrome wasn’t even a diagnosis at that point,” Dawn Sensenig says. “They had no idea what to expect. She spent so much time in different hospitals, and we’ve been able to prevent all that because we know the diagnosis.”
Williams, despite becoming CSC’s third pediatrician only two years ago, waxes historic.
“There are many examples of disorders like Jessica’s that were once a mystery to doctors and families,” she says. “The work at the clinic helps the families put a name to something they’ve been struggling with all those years, and in many cases it gives them hope and a therapy to help treat their child.”
Inspired By Morton’s Vision, Spinoffs Extend Care to Plain Communities
If imitation is the highest form of flattery, then D. Holmes Morton’s efforts to identify and treat genetic illnesses among the Amish and Mennonite communities are unmistakably blush-worthy.
In the 26 years since Morton and his wife, Caroline, co-founded the Clinic for Special Children (CSC) in Lancaster County, Pennsylvania, a handful of near-replicas have cropped up in Ohio, Indiana, and Wisconsin — states pocketed with some of the highest concentrations of so-called Plain people, who total about 728,000 in the United States.
The later clinics are not exact clones of the CSC, but their founders have told Morton how his vision helped shape and refine their own focus on Amish and Mennonites, who suffer disproportionately from genetic illnesses because they are descendants of small, separate groups of European settlers who emigrated to the U.S. in the 1700s. The CSC has even spawned its own offspring, a clinic designed for both children and adults in Belleville, Pennsylvania, 115 miles west of the original clinic.
“It was always the mission of this clinic to help get other places established,” Morton explains. “So, all of these clinics have been, in a sense, spinoffs, and I see them as collaborators.”
Care Modeled on Specific Needs of Amish and Mennonite PatientsEach of the clinics modeled after Morton’s facility reflects its own specific populations of Amish and Mennonites and, like the CSC, often serves non-Plain patients with unusual genetic diseases who hail from other states and countries.
“There’s some overlap, but a lot of diseases are unique for each community,” says Heng Wang, medical director of the DDC Clinic- Center for Special Needs Children in Middlefield, Ohio. DDC patients, for example, include a large number with Cohen syndrome, caused by a mutation in the VPS13B gene and characterized by small head size, weak muscle tone, and intellectual disability.
The DDC Clinic opened in 2002 after a group of Amish from northeast Ohio made a pilgrimage to the CSC to find answers to their children’s baffling set of unidentified disorders. Morton shut down his own clinic for two days to consult with the families, recommending they set up a similar facility to meet their needs. The DDC, which moved into expanded quarters in 2009 and has served more than 500 patients, has since developed more than 30 DNA tests for rare diseases.
A trio of other facilities has opened in the last several years, including the Indiana-based Community Health Clinic; La Farge Medical Clinic-VMH in Wisconsin; and New Leaf Center in Mt. Eaton, Ohio. Combining features such as genetic testing, ongoing medical monitoring, birthing centers, and dental care — the CSC itself lacks the latter two services — these clinics have propelled Morton’s plans for his new spinoff.
Success of Old Clinic Spurs Need for New
“Twenty-five years later, the children we took care of are no longer children,” Morton says with a smile.