Researchers from Children’s Hospital of Philadelphia (CHOP) and the Clinic for Special Children have found that complement factor I (CFI) deficiency, a rare genetic disorder linked to neuroinflammation, is significantly more common in individuals of Old Order Amish ancestry compared to the global population. The study, published in the Journal of Allergy and Clinical Immunology, shows that CFI deficiency occurs at a rate more than 4,500 times higher among Old Order Amish than elsewhere.
CFI deficiency affects the immune system and can lead to recurrent bacterial infections as well as vascular and neuroinflammatory symptoms. While globally it affects fewer than one in a million births, within the Old Order Amish community the prevalence is about 1 in 730. Researchers note that both genetic factors and environmental influences may impact how the disease develops.
The investigation began when an Old Order Amish patient was treated at CHOP for acute neuroinflammatory symptoms with no clear cause. Rapid exome sequencing revealed a variant in the CFI gene responsible for her illness. This led researchers to look for similar cases within the community due to their shared genetic background and lifestyle. Additional cases were identified, indicating that this variant is relatively common among Old Order Amish.
“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 collaboration between CHOP and Clinic for Special Children expanded after this initial case.
Neil D. Romberg, MD said: “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.”
Laura Poskitt, DO added: “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.”
In reviewing cases among eleven affected Amish patients carrying this variant studied by researchers from both institutions https://www.chop.edu/, five had experienced severe neuroinflammatory events but recovered after receiving high-dose steroids or eculizumab.
Whitney Reid, MD commented: “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.”
Carson emphasized: “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 disease.”
The research received support from several organizations including grants from National Institutes of Health’s National Institute of Allergy and Infectious Diseases.
