Children's Hospital of Philadelphia, Clinic for Special Children Discover Ultra Rare Form of Neuroinflammatory Disease is Much More Common in Old Order Amish than General Population

By working closely with the Amish community, clinicians are able to gather the critical information to effectively treat patients with a genetic neuroinflammatory condition

PHILADELPHIA and GORDONVILLE, Pa., Aug. 12, 2025 /PRNewswire/ -- Researchers from Children's Hospital of Philadelphia (CHOP) and the Clinic for Special Children found that complement factor I (CFI) deficiency, an ultra-rare genetic disorder that can cause debilitating neuroinflammation, is more than 4500 times more likely to be found in individuals of Old Order Amish ancestry than the rest of the global population. These findings could help clinicians better recognize the disease and develop a standard-of-care, particularly for Amish patients affected by this disease. The findings were published today by the Journal of Allergy and Clinical Immunology.

CFI deficiency is a genetic disorder that affects the immune system, often resulting in a high likelihood of recurrent bacterial infections, and in some cases, vascular and neuroinflammatory symptoms requiring hospitalization and acute management. In addition to genetic factors, ethnic background or epigenetic influences like lifestyle, environmental exposures and diet can influence the trajectory of the disease, which is estimated worldwide to affect fewer than one in a million births but as high as 1 in 730 members of the Old Order Amish community.

The Clinic for Special Children, which provides clinical care to children and adults with complex medical disorders and has a specific focus on the treatment and research of disorders affecting the Old Order Amish and Mennonite communities, was alerted to an Old Order Amish patient at CHOP presenting with acute neuroinflammatory symptoms of unknown cause. Rapid exome sequencing identified a variant of unknown significance in the gene CFI, which was found to be the underlying cause of her disease and directed her targeted management and recovery. This case motivated researchers to determine if other members of the Old Order Amish community also harbored this genetic finding, as they share a common genetic heritage, agrarian lifestyle, and environmental exposures. Further investigtion found it was quite common and contributed to disease in the multiple Amish individuals.

"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. She was transferred to CHOP due to the severity of her condition and ultimately needed neurosurgical intervention," said co-senior study author Vincent J. Carson, MD, a pediatric neurologist with the Clinic for Special Children. "Rapid exome sequencing, which can provide genetic diagnoses in a matter of days, was done at CHOP and confirmed the diagnosis of CFI deficiency. As a result, she was treated with a specific monoclonal antibody that blocks the complement cascade, called Eculizumab. This resulted in the resolution of the brain inflammation, leading to a full recovery."

The Clinic for Special Children knew that patients with Old Order Amish ancestry carried the CFI gene, but did not yet know that a particular variant caused disease. This led to a collaboration between the Clinic for Special Children and CHOP to learn more about the incidence of brain inflammation in CFI deficiency.

"What started as a case report turned into a population study," said co-senior study author Neil D. Romberg, MD, an attending physician with the Division of Allergy and Immunology at CHOP. "There is a striking level of enrichment of this genetic variant in the Amish community, and 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."

"There are about 430 genetic disorders that we treat and counting, and since hundreds of thousands of Amish and Mennonites living in this country can trace their ancestry back to about 80 Amish founders and 240 Mennonite effective founders, we know that certain disorders are much more prevalent while others that are more common in the general population rarely affect this community," said Laura Poskitt, DO, medical director of the Clinic for Special Children. "With the consent of our patient communities, we've been able to maintain a database that helps us learn more about genetic variants that may be more common in these patients in particular."

When focusing on 11 Amish patients who had this variant, five of the patients had presented with critical neuroinflammatory diagnoses. Those patients recovered with the aid of high dose steroids, and one patient had a clinical response to eculizumab, a monoclonal antibody used to treat several diseases linked to the immune system.

"We have heard from patients treated for this disease that they've been able to recover and get back to being active members of their community, so we want to make sure we can properly identify any potentially affected patient and provide them with effective options for managing this disorder," said first study author Whitney Reid, MD, an attending physician in the Division of Allergy and Immunology at CHOP. "In speaking with this community, they are asking good questions and want to be involved in ways that can not only help affected Amish but anyone who is impacted by this disease."

"Getting to the root cause of the disease is a game changer," Carson said. "All patients with inflammation of the brain or spinal cord who have Amish heritage should be tested for CFI deficiency. Knowing this allows us to use targeted treatments, such as eculizumab, and change the course of the disease."

This study was supported by the National Institutes of Health, National Institute of Allergy and Infectious Diseases grants AI146026, AI184976 and AI179680, the Jeffrey Modell Foundation , the Gail B. Slap Department of Pediatrics Fellowship Award, the Ruth L. Kirschstein T32 National Research Service Award, the Dr. Steven Douglas Memorial Fund and the Sayer family.

Reid et al, "Complement Factor I Deficiency-Associated Neuroinflammatory Disease Among Old Order Amish." J Allergy Clin Immunol. Online June 29, 2025. DOI: 10.1016/j.jaci.2025.06.021.

About Children's Hospital of Philadelphia: 
A non-profit, charitable organization, Children's Hospital of Philadelphia was founded in 1855 as the nation's first pediatric hospital. Through its long-standing commitment to providing exceptional patient care, training new generations of pediatric healthcare professionals, and pioneering major research initiatives, the hospital has fostered many discoveries that have benefited children worldwide. Its pediatric research program is among the largest in the country. The institution has a well-established history of providing advanced pediatric care close to home through its CHOP Care Network, which includes more than 50 primary care practices, specialty care and surgical centers, urgent care centers, and community hospital alliances throughout Pennsylvania and New Jersey. CHOP also operates the Middleman Family Pavilion and its dedicated pediatric emergency department in King of Prussia, the Behavioral Health and Crisis Center (including a 24/7 Crisis Response Center) and the Center for Advanced Behavioral Healthcare, a mental health outpatient facility. Its unique family-centered care and public service programs have brought Children's Hospital of Philadelphia recognition as a leading advocate for children and adolescents. For more information, visit https://www.chop.edu.

About the Clinic for Special Children: The Clinic for Special Children is a non-profit organization located in Lancaster County, PA, that provides primary care and advanced laboratory services to children and adults who live with genetic or other complex medical disorders. Founded in 1989, the organization provides services to over 1,700 individuals and is recognized as a world leader in translational and precision medicine. The organization is primarily supported through community fundraising events and donations. For more information, please visit www.ClinicforSpecialChildren.org.

Contact: Amanda DiPaolo Bradley
Children's Hospital of Philadelphia
(267)391-8599
[email protected]

Kelly Cullen
Clinic for Special Children
[email protected]

SOURCE Children's Hospital of Philadelphia