X-linked sideroblastic anemias (XLSA) are characterized by impaired mitochondrial iron metabolism, “ringed” sideroblasts and increased erythropoiesis. In some cases, these disorders cause parenchymal iron overload similar to that of hemochromatosis. Increased iron absorption is upregulated by relative or absolute suppression of hepcidin expression presumably mediated by ineffective erythropoiesis through growth/differentiation factor 15 (GDF15). Iron overload in some patients is exacerbated by erythrocyte transfusion. Mutations in the ALAS2 gene that encodes erythroid-specific 5-aminolevulinate synthase (ALA synthase) account for most cases (OMIM #300751), although rare mutations in other genes on the X chromosome or elsewhere also cause sideroblastic anemia phenotypes and variable degrees of iron loading. Anemia in two-thirds of patients with ALAS2 mutations can be alleviated with simple, non-transfusion therapy. Early recognition and treatment of iron accumulation prevents irreversible organ damage. Informal experience suggests that XLSA may be more common than is generally recognized.

ALAS2 sideroblastic anemia

History

In 1945, Thomas Cooley described the first cases of XLSA in two brothers from a large family in which the inheritance of the condition was documented through six generations. Additional observations in this family and description of a new kinship were published by Rundles and Falls in 1946. In 1956, Harris and co-workers reported the first case of “pyridoxine-responsive anemia.” Ringed sideroblasts were described by Bjorkman in 1956 (Fig. 25.1). Byrd and Cooper coined the term “hereditary iron-loading anemia” in 1961. The term “sideroblastic anemia” was adopted in 1965. By this time, the association of anemia sometimes responsive to pyridoxine and iron overload were widely recognized.