Photo Credit: iStock.com/Pitju

A rare CFI variant linked to severe neuroinflammation was found to be highly enriched in the Old Order Amish population.  

A study published in June 2025 issue of Journal of Allergy and clinical Immunology highlighted complement factor I (CFI) deficiency as an ultra-rare inherited disorder of complement regulation characterized by diverse infectious, vasculitic, and neuroinflammatory manifestations.  

Researchers conducted a retrospective study to functionally validate the previously unrecognized disease-associated CFI variant (Y₄₅₉ S) and examine its enrichment in the Old Order Amish population.  

They assessed the expression and function of the Y₄₅₉ S CFI variant using immunoblotting, complement factor 3b degradation assays, and crystal structure analysis. Variant frequencies in the Old Order Amish population were identified through genomic data. Patient samples were analyzed in clinical laboratories for leukocyte subsets, cytokine levels, and concentrations of complement components. Brain and spine MRIs were reviewed for neuroinflammatory features by a neuroradiologist.  

The results showed that the Y₄₅₉ S variant led to a loss of function in CFI. The CFI Y₄₅₉ S allele was over 4,500-fold more frequent in the Old Order Amish, with a mean allelic frequency of 0.037. It was estimated that 1 in every 730 live births in this group would be homozygous for the variant. In a single-center cohort of 11 Amish individuals homozygous for CFI Y459S, 5 had serious neuroinflammatory conditions such as acute disseminated encephalomyelitis, transverse myelitis, and aseptic meningoencephalitis. Common findings included neutrophilic pleocytosis in the cerebrospinal fluid, ongoing complement activation, female predominance, variable MRI features, and, in 1 case, clinical improvement with eculizumab.  

Investigators concluded that CFI deficiency was an important diagnostic consideration in individuals with neuroinflammatory symptoms, neutrophilic cerebrospinal fluid pleocytosis, and complement consumption, particularly among the Old Order Amish community. 

Source:  jacionline.org/article/S0091-6749(25)00698-0/abstract