Abnormalities of flavin monooxygenase as an etiology for sideroblastic anemia

We postulated that a deficiency of flavin monooxygenase (FMO)-a ferrireduct ase component of cells-could produce sideroblastic anemia. FMO is an intrac ellular ferrireductase which may be responsible for the obligatory reductio n of ferric to ferrous iron so that reduced iron can be incorporated into h eme by ferrochelatase. Abnormalities of this mechanism could result in accu mulation of excess ferric iron in mitochondria of erythroid cells to produc e ringed sideroblasts and impair hemoglobin synthesis, To investigate this hypothesis we obtained blood from patients with sideroblastic anemia and no rmal subjects. Extracts of peripheral blood lymphocytes were used to measur e ferrireduction by utilization of NADPH, Lymphoid precursors are reported to accumulate iron in mitochondria similarly to erythroid precursors. Utili zation of lymphoid precursors avoided the need for bone marrow aspirations, We studied three patients with sideroblastic anemia, One patient and his a symptomatic daughter had a significant decrease in ferrireductase activity. They also had markedly diminished concentrations of FMO in lymphocyte prot ein extracts on Western blots. This was accompanied by increased concentrat ion of mobilferrin in the extracts. These results suggest that abnormalitie s of FMO and mobilferrin may cause sideroblastic anemia and erythropoietic hemochromatosis in some patients. (C) 2000 Wiley-Liss, Inc.