Complement factor I deficiency-associated neuroinflammatory disease among Old Order Amish.

Area of Science:

• Immunology
• Genetics
• Neurology

Background:

• Complement factor I (CFI) deficiency is a rare genetic disorder affecting complement regulation.
• It presents with diverse symptoms including infections, vasculitis, and neuroinflammation.

Purpose of the Study:

• To functionally validate a novel disease-associated CFI variant (Y459S).
• To investigate the prevalence of this CFI variant in the Old Order Amish population.

Main Methods:

• Functional assessment of CFI Y459S using immunoblot, C3b degradation assays, and crystal structure analysis.
• Genomic database analysis to determine CFI variant frequencies in Old Order Amish populations.
• Clinical laboratory assessment of patient samples for immune cell counts, cytokines, and complement levels.
• Neuroradiological review of MRI scans for neuroinflammatory changes.

Main Results:

• The Y459S variant results in a loss of CFI function.
• CFI Y459S allele is significantly enriched in the Old Order Amish (4500-fold increase).
• Homozygosity for Y459S is predicted in 1 in 730 live births in this population.
• Five out of 11 Amish patients with homozygous Y459S presented with severe neuroinflammatory conditions.
• Neuroinflammation in these patients featured neutrophilic pleocytosis, complement activation, and diverse MRI findings.

Conclusions:

• CFI deficiency is a critical diagnostic consideration for neuroinflammatory conditions.
• Neutrophilic CSF pleocytosis and complement consumption are key indicators.
• Individuals from the Old Order Amish community with these symptoms warrant specific genetic screening for CFI deficiency.