PHILADELPHIA, PA and GORDONVILLE, PA — A new study from Children’s Hospital of Philadelphia (CHOP) and the Clinic for Special Children has revealed that complement factor I (CFI) deficiency, an exceptionally rare immune disorder, occurs at rates more than 4,500 times higher in Old Order Amish populations than in the global population. The findings, published August 12, 2025, in the Journal of Allergy and Clinical Immunology, could reshape how physicians diagnose and treat the condition, particularly in Amish communities.
CFI deficiency impairs the immune system’s ability to regulate inflammation, leaving patients vulnerable to recurrent bacterial infections as well as severe vascular and neuroinflammatory episodes. Globally, the condition is estimated to affect fewer than one in a million births. Yet among the Old Order Amish, researchers estimate the prevalence may be as high as one in 730 individuals.
The study was prompted after an Amish patient at CHOP presented with sudden, severe neuroinflammatory symptoms. Genetic testing confirmed a CFI mutation, guiding targeted treatment with the monoclonal antibody eculizumab, which successfully reversed her brain inflammation. The case led researchers to investigate further and uncover a broader pattern within the community.
“The first patient presented with headache, decreased consciousness, and weakness on one side of her body, which an MRI confirmed was due to brain inflammation,” said Dr. Vincent J. Carson, pediatric neurologist at the Clinic for Special Children and co-senior study author. “Rapid exome sequencing confirmed the diagnosis of CFI deficiency, and treatment with eculizumab resulted in a full recovery.”
Subsequent testing identified the same variant in 11 additional Amish patients. Nearly half had developed serious neuroinflammatory disease requiring hospitalization. Most responded to high-dose steroids, while one benefited from eculizumab therapy.
Dr. Neil D. Romberg, co-senior study author and attending physician at CHOP, emphasized the significance of the discovery. “There is a striking level of enrichment of this genetic variant in the Amish community,” Romberg said. “Now that our understanding of this disease in this population has been expanded, we can offer personalized treatment plans for these patients to help them recover and get back to a normal life within their community.”
The research underscores the importance of genetic heritage in disease prevalence. The Old Order Amish and Mennonite populations in the U.S. trace their ancestry to a limited number of founders, contributing to the higher frequency of certain rare disorders. The Clinic for Special Children maintains a genetic database, with patient consent, to track and better understand these conditions.
Laura Poskitt, DO, medical director at the Clinic, noted that the database has been critical in identifying unique health risks in these communities. “Since hundreds of thousands of Amish and Mennonites trace back to a small group of founders, we know that some disorders are far more common, while others rarely appear in this community,” she said.
The study’s authors stress that early recognition of CFI deficiency is key, as rapid diagnosis can allow for targeted interventions that prevent lasting neurological damage.
“All patients with inflammation of the brain or spinal cord who have Amish heritage should be tested for CFI deficiency,” Carson said. “Knowing this allows us to use targeted treatments, such as eculizumab, and change the course of the disease.”
The research was supported by the National Institutes of Health and several foundations, including the Jeffrey Modell Foundation and the Dr. Steven Douglas Memorial Fund.
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