A 28-year-old woman presents with hemolytic anemia, thrombosis and recurrent pregnancy loss. Flow cytometry on peripheral blood erythrocytes shows markedly decreased CD59 and CD55 expression on a major clone. Which mechanism is responsible for the complement sensitivity in this condition?

• A Germline deletion of CFHR1/CFHR3 genes leading to factor H deficiency
• B Autoantibody against complement regulatory protein CD46 (MCP)
• C Acquired somatic mutation in PIG-A gene disrupting GPI-anchor biosynthesis ✓
• D Gain-of-function mutation in C3 causing spontaneous C3 tick-over

Explanation

Paroxysmal nocturnal hemoglobinuria (PNH) results from an acquired somatic mutation in the X-linked PIG-A gene in a hematopoietic stem cell. PIG-A is essential for the first step in GPI-anchor synthesis; its loss prevents surface expression of all GPI-anchored proteins including CD59 (protectin, blocks MAC) and CD55 (DAF, accelerates C3 convertase decay). Without these regulators, complement cascades to lysis on the cell surface. CFHR1/3 deletion causes atypical HUS; CD46 autoantibodies cause a complement dysregulation phenotype; C3 gain-of-function mutations also underlie C3 glomerulopathy.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.