GPI (glucose-6-phosphate isomerase) catalyzes the interconversion of glucose-6-phosphate and fructose-6-phosphate, a key step in glycolysis and gluconeogenesis. Beyond its metabolic role, GPI functions extracellularly as a cytokine with multiple immunological and neurological activities. It acts as autocrine motility factor, enhancing endothelial cell migration, and as neuroleukin, a neurotrophic factor supporting spinal and sensory neuron survival 1. GPI is released by lectin-stimulated T cells to induce immunoglobulin secretion 2. Loss-of-function mutations in GPI cause hemolytic anemias and congenital dyserythropoietic anemias. A stable GPI variant associated with severe hemolytic anemia, mental retardation, and muscular hypotonia demonstrated altered substrate affinities 3, indicating that even structurally stable enzyme variants can produce clinical disease through kinetic alterations. GPI deficiency presents across a spectrum of disorders including non-spherocytic hemolytic anemia, intellectual disability, and thrombocytopenia, highlighting the gene's essential role in both erythropoiesis and broader cellular metabolism. The diversity of disease presentations reflects GPI's dual function as both a glycolytic enzyme and an extracellular signaling factor.