Hereditary sideroblastic anemias: pathophysiology, diagnosis, and treatment.
Inherited sideroblastic anemia comprises several rare anemias due to heterogeneous genetic lesions, all characterized by the presence of ringed sideroblasts in the bone marrow. This morphological aspect reflects abnormal mitochondrial iron utilization by the erythroid precursors. The most common X-linked sideroblastic anemia (XLSA), due to mutations of the first enzyme of the heme synthetic pathway, delta-aminolevulinic acid synthase 2 (ALAS2), has linked heme deficiency to mitochondrial iron accumulation. The identification of other genes, such as adenosine triphosphate (ATP) binding cassette B7 (ABCB7) and glutaredoxin 5 (GLRX5), has strengthened the role of iron sulfur cluster biogenesis in sideroblast formation and revealed a complex interplay between pathways of mitochondrial iron utilization and cytosolic iron sensing by the iron-regulatory proteins (IRPs). As recently occurred with the discovery of the SLC25A38-related sideroblastic anemia, the identification of the genes responsible for as yet uncharacterized forms will provide further insights into mitochondrial iron metabolism of erythroid cells and the pathophysiology of sideroblastic anemia.
Vita-Salute University and San Raffaele Scientific Institute, Milan, Italy. clara.camaschella@hsr.it
Clara
C
Camaschella
D000624:5-Aminolevulinate Synthetase / Q000235:genetics; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D000756:Anemia, Sideroblastic / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D003131:Combined Modality Therapy; D041905:Erythroid Cells / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D054477:Glutaredoxins / Q000235:genetics; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I / Q000235:genetics; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000097:blood / Q000175:diagnosis / Q000235:genetics* / Q000503:physiopathology / Q000628:therapy; D008565:Membrane Proteins / Q000235:genetics; D008928:Mitochondria / Q000378:metabolism; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D016896:Treatment Outcome
C113037:ABCB7 protein, human; D018528:ATP-Binding Cassette Transporters; C516011:GLRX5 protein, human; D054477:Glutaredoxins; C103673:HFE protein, human; D000071020:Hemochromatosis Protein; D015395:Histocompatibility Antigens Class I; D008565:Membrane Proteins; D007501:Iron; D000624:5-Aminolevulinate Synthetase; C480079:ALAS2 protein, human