When an Amish patient arrived at the Children’s Hospital of Philadelphia with fatigue, a severe headache, and weakness on one side of her body, doctors scrambled to find a cause.
All they could see was that she had brain inflammation. That’s usually caused by an infection, but her tests came back normal. High dose steroids, a standard treatment, weren’t effective.
By that point, the girl’s brain was so swollen physicians had to remove part of her skull to relieve the pressure, which had put her at risk of brain damage.
She was “critically ill,” recalled Whitney Reid, an immunologist and one of her doctors at CHOP.
Frustrated and lacking answers, her doctors sequenced her DNA. They found she had an ultra-rare genetic disorder in which the immune system becomes dysfunctional.
The disorder, complement factor I deficiency, is caused by mutations in a gene that would normally regulate part of the immune system.
It can cause harmful inflammation, particularly in the brain and spinal cord. That can present as a fever, nausea, confusion, dizziness, and even numbness. The condition also leads to recurrent bacterial infections.
Complement factor I deficiency is so rare it affects fewer than one in a million people born worldwide.
The discovery spurred the Clinic for Special Children, an independent clinic in Lancaster County dedicated to treating patients with rare genetic disorders, to test several more Amish patients for the disorder.
Soon, physicians had identified a cluster of cases, leading doctors at CHOP and the Clinic to another surprising finding: Among the Old Order Amish, the largest group of Amish people, the disorder is estimated to affect as many as 1 in 730 people. That’s because mutations causing the disorder are more than 4,500 times more common in this group than in the general population.
This statistic, reported in a new study in the Journal of Allergy and Clinical Immunology, led doctors to revisit past instances of brain inflammation in Amish patients, and ultimately solve a yearslong medical mystery.
An undiagnosed mystery
Amish patients had been showing up at the Clinic for Special Children and nearby hospitals with brain inflammation for years. Doctors couldn’t figure out what was causing it. They would simply treat the patients and send them home once the symptoms resolved.
Many likely had complement factor I deficiency, but were undiagnosed, said Vincent Carson, a pediatric neurologist at the Clinic and co-senior author on the study.
“Nobody was looking for it,” he said.
After CHOP diagnosed the Amish girl in 2021 with the disorder, doctors began to test symptomatic Amish patients for the disorder. Carson even sent messages out to colleagues around the country alerting them to do the same.
“When they identified this in the first patient, that then made us look at anybody from the Amish community through a different lens,” Carson said.
This isn’t the first genetic disorder to be overrepresented in the Amish community. The Clinic was specifically founded in 1989 in response to higher rates of rare genetic diseases in Amish and Mennonite people. Some of the most notable are a type of dwarfism called Ellis-van Creveld syndrome and assorted metabolic disorders.
The reason for this comes down to a phenomenon called the “founder effect,” which happens when a small number of individuals isolate from the larger population. Over generations, this leads to less genetic diversity, with the genes of the “founders” becoming disproportionately present in the community.
It’s kind of like if you took a crayon pack, picked just a few colors, and threw the rest away. All your drawings will be some combination of those colors from now on.
Most of the approximately 400,000 Amish people in America descend from just a few hundred settlers who immigrated to the United States in the 18th century. Any errors in the genetic code of those original members were more likely to spread.
That includes the genetic mutation that causes complement factor I deficiency.
A dysfunctional immune system
The disorder affects a group of proteins in the immune system that help clear bacteria and viruses from the body. Known as “the complement system,” it helps fight infection, but should only be turned on when there’s an active threat. Otherwise, it could cause damage to healthy cells.
People with the disorder lack a protein called “complement factor I,” which normally turns the system off when it’s not needed. This results in the complement system running wild, like a car without a brake.
“If a patient is missing that protein, they could be predisposed to having that part of the immune system attack their own bodies,” said Reid, who was first author on the study.
Amish families would often share stories of kids being more sick than their siblings, and having a history of pneumonia, ear infections, and even infections that turned fatal, Carson said. Those were likely undiagnosed cases of the disorder.
Reid and Carson recently held a family education day at the Clinic for the Amish community to learn more about complement factor I deficiency. They emphasized the importance of couples with a family history doing genetic testing to see if they have the mutation.
Knowing you have the disease could help families watch out for potentially dangerous symptoms.
For example, doctors can give families an emergency plan if their child has a fever, including antibiotics to use at home. Additional vaccines could be given to help prevent dangerous infections caused by pneumococcal and meningococcal bacteria.
They could also warn parents to seek care quickly if a child has a bad headache or is more tired than usual, because that could indicate inflammation.
For unknown reasons, this symptom seems to occur mostly in females, starting in their teenage years.
The Amish girl at CHOP was only 17 when brain inflammation landed her in the intensive care unit. In addition to getting skull surgery and steroids, she received therapeutic cooling and blood plasma exchange.
At first, these treatments seemed to work, but then her symptoms returned, including a fever, vomiting, altered mental status, and dizziness.
Once doctors found out she had complement factor I deficiency, that helped them find the right medicine to treat her. They chose a drug called eculizumab, which inhibits the complement system.
Within a day or two, she recovered.
“She is perfectly fine, and is a schoolteacher living her life very happily,” said Reid, who saw her a few weeks ago along with Carson.
“You wouldn’t even know that she went through such an ordeal,” Carson added.
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