Complement factor I deficiency–associated neuroinflammatory disease among Old Order Amish

Background: Complement factor I (CFI) deficiency is an ultrarare inborn disorder of complement regulation that manifests with protean infectious, vasculitic, and neuroinflammatory symptoms. Objective: We sought to functionally validate a previously unrecognized, disease-associated CFI variant (Y459S) and determine variant enrichment in the Old Order Amish population. Methods: Expression and function of the CFI Y459S variant was evaluated via immunoblot, complement factor 3b degradation, and crystal structure analysis. CFI variant frequencies in Old Order Amish populations were determined using genomic databases hosted by the Clinic for Special Children and the Anabaptist Variant Server. Patient samples were assessed for leukocyte frequencies, cytokine concentrations, and complement component concentrations in clinical laboratories. Neuroinflammatory assessments were made by review of brain and spine magnetic resonance imaging by a blinded neuroradiologist. Results: Y459S conferred a loss of function to CFI. The CFI Y459S allele is enriched more than 4500-fold among the Old Order Amish (mean allelic frequency, 0.037), with 1 in every 730 live births in this population predicted to be homozygous. A single-center cohort of 11 Amish CFI Y459S homozygous patients identified 5 patients with critical neuroinflammatory diagnoses including acute disseminated encephalomyelitis, transverse myelitis, and aseptic meningoencephalitis. Features of CFI-deficient neuroinflammation included neutrophilic cerebral spinal fluid pleocytosis, constitutive complement activation, female predominance, diverse neuroimaging findings, and (in 1 case) a clinical response to eculizumab. Conclusions: CFI deficiency should be a key diagnostic consideration for patients with neuroinflammatory symptoms, neutrophilic cerebral spinal fluid pleocytosis, and complement consumption, especially if they belong to the Old Order Amish community.