Porphyrin Synthesis and Heme Synthetase Activity in Pyridoxine-Responsive Anemia

Previous in vitro studies had shown that reticulocytes from a patient with pyridoxine-responsive anemia (PRA) incorporated glycine-2-¹⁴C into heme at 11-25 per cent of the normal rate. Incorporation of the intermediate compound, δ-aminolevulinic acid-4-¹⁴C (ALA), varied from 46 to 81 per cent of normal. These findings suggested two defects in the synthesis of heme: a major one prior to formation of ALA, probably ALA synthetase, and a minor one somewhere between ALA and heme. This minor defect was investigated in a patient with PRA during a period of repeated phlebotomies resulting in a 30 gram reduction in iron stores. Porphyrin synthesis from ALA was measured in vitro and found to be normal. Heme synthetase activity in particulate fractions of reticulocytes measured by radioiron incorporation into heme was 50 per cent less than normal when the iron stores were high and significantly improved when the iron stores were reduced to normal. Repeat studies showed that incorporation of ALA-4-¹⁴C into heme by intact reticulocytes equaled the normal rate. Glycine incorporation was still reduced. Concomitant with the improvement in heme synthetase activity was an improvement in anemia. These results suggest that excess iron is a significant cause of the reduced heme synthetase activity observed in this patient with pyridoxine-responsive anemia.