The molecular basis of the sideroblastic anemias

The sideroblastic anemias display remarkable clinical and hematologic heterogeneity but share in common mitochondrial iron loading as evidence of unhinging between intracellular iron metabolism and heme biosynthesis. Molecular defects responsible for this unhinging have now been identified and appear to display matching heterogeneity. Mutations in the erythroid-specific ALA synthase 2 (ALAS2) gene cause microcytic anemia, whereas mitochondrial DNA deletions are responsible for Pearsons syndrome with a macrocytic anemia. The molecular basis for other causes including X-linked non-ALAS2-associated autosomal inheritance and for the more frequent acquired forms of this disorder awaits discovery. Speculation about their causes includes disturbed intracellular iron homeostasis involving iron-responsive factors involved in the translational control of ALAS2 and in certain nuclear and mitochondrial genes important for erythroid mitochondrial metabolism.