Researchers find CFI deficiency alarmingly high in old order Amish

Researchers from the 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 in 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 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 investigation found it was quite common and contributed to the disease in 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.”

Vincent J. Carson, MD, Study Co-Senior Author and Pediatric Neurologist, Clinic for Special Children

He added, “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.”