Elsevier

Seminars in Hematology

Volume 46, Issue 4, October 2009, Pages 371-377
Seminars in Hematology

Hereditary Sideroblastic Anemias: Pathophysiology, Diagnosis, and Treatment

https://doi.org/10.1053/j.seminhematol.2009.07.001Get rights and content

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.

Section snippets

Classification of Inherited Sideroblastic Anemias

A current classification of inherited sideroblastic anemias, the involved genes, and the hematological features are summarized in Table 1. X-linked sideroblastic anemia (XLSA) and X-linked sideroblastic anemia with ataxia (XLSA/A) are well characterized. Glutaredoxin 5 (GLRX5)- and SLC25A38-related defects have been recently identified, whereas the genetic defects in other forms remain unknown. Some rare syndromic sideroblastic anemias are associated with alterations of mitochondrial DNA.

Pathophysiology of Anemia

In ALAS2-related forms, anemia is related to deficient heme formation. It is likely that in the novel type due to SLC25A38 mutations the defect may also be ascribed to heme deficiency, although it is not yet confirmed that the amino acid transporter encoded by SLC25A38 facilitates import of glycine to the mitochondria for ALA formation.22 Also, ABCB7 and GLRX5 mutations ultimately cause heme deficiency, although through different primary defects. As clearly shown in the zebrafish shiraz model,29

Diagnosis

The diagnosis of sideroblastic anemia requires the presence of ringed sideroblasts in the bone marrow. The term “sideroblast” refers to normal immature erythroblasts (blasts) that contain visible Perl's positive (sideros) inclusions. The ring should cover at least one third of the nucleus rim. The erythrocytes that contain iron inclusions, Pappenheimer bodies, are called “siderocytes.” Cytofluorimetric approaches to reveal mitochondrial ferritin expression have been successfully used for

Treatment

Asymptomatic or mildly anemic patients require only follow-up. Oral pyridoxine (50-100 mg/d) supplementation should be always attempted in XLSA, since in some cases hemoglobin attains normal levels, whereas in others a partial correction of anemia is observed.13 Low pyridoxine doses should be administered in responders as maintenance therapy to avoid recurrence of anemia. Anemia in XLSA/ataxia is pyridoxine-unresponsive, but since it is usually mild, does not require any treatment. Transfusions

Conclusions

Several advances have been achieved applying molecular genetics to the study of the complex chapter of inherited sideroblastic anemias in the last years. The genetic heterogeneity of these disorders has been dissected and new types have been recognized, leading to an increased understanding of the pathogenesis of the iron accumulation in erythroid cells and of the iron utilization by the erythroid mitochondria. It is expected that the definition of the defects of the remaining unclassified

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