The genetics of inherited sideroblastic anemias

The sideroblastic anemias are a heterogeneous group of acquired and inherited bone marrow disorders defined by the presence of pathologic iron deposits in erythroblast mitochondria. While the pathogenesis of almost all cases of acquired sideroblastic anemia is unknown, the molecular genetic basis for several of the inherited forms have now been described. Initially, mutations in ALAS2 in X-linked sideroblastic anemia (XLSA) focused attention on the heme biosynthetic pathway as a primary cause of sideroblastic anemia. However, the subsequent description of the genes involved in XLSA with ataxia, thiamine-responsive megaloblastic anemia, and Pearson marrow-pancreas syndrome have implicated other pathways, including mitochondrial oxidative phosphorylation, thiamine metabolism, and iron-sulfur cluster biosynthesis, as primary defects in sideroblastic anemias that may only secondarily impact heme metabolism.