Hereditary Sideroblastic Anemias: Pathophysiology, Diagnosis, and Treatment
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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Congenital sideroblastic anemia in a child with biliary atresia: An association?
2023, Pediatric Hematology Oncology JournalRegulation and tissue-specific expression of δ-aminolevulinic acid synthases in non-syndromic sideroblastic anemias and porphyrias
2019, Molecular Genetics and MetabolismDefining the Boundary Between Myelodysplastic Syndromes and Myeloproliferative Neoplasms
2019, Surgical Pathology ClinicsCitation Excerpt :MDS/MPN RS-T should be distinguished from other non-neoplastic conditions associated with increased ring sideroblasts. These include excessive alcohol consumption, lead poisoning, copper and pyridoxine deficiency, isoniazid therapy, and congenital sideroblastic anemia.83 Like other hematological malignancies, the 2017 WHO classification allows an unclassifiable category to include cases that have hybrid MDS and MPN clinical features, but do not fit into any specific type of well-defined MDS/MPN, namely CMML, aCML, JMML, and MDS/MPN-RS-T.
Molecular pathophysiology and genetic mutations in congenital sideroblastic anemia
2019, Free Radical Biology and MedicineCitation Excerpt :Hence, this review summarizes the recent progress in the molecular genetics, pathophysiology, and clinical features of CSA. As mentioned earlier, CSA is caused by the mutation in genes involved in heme biosynthesis, Fe–S cluster biosynthesis, and mitochondrial protein synthesis (Table 1) [1–5]. In addition, the presence of nonhematopoietic complications differentiates syndromic CSAs from nonsyndromic CSAs, depending on the kind of genes mutated (Table 1).
Congenital sideroblastic anemia: Advances in gene mutations and pathophysiology
2018, GeneCitation Excerpt :Sideroblastic anemia consists of congenital and acquired sideroblastic anemia, congenital sideroblastic anemia (CSA) comprise a series of sideroblastic anemia caused by iron metabolism related genes mutation, can be classified into three types according to pathophysiology: mutations of genes involved in heme synthesis, iron‑sulfur (Fe-S) cluster synthesis and transportation, mitochondrial respiratory chain synthesis(Fujiwara and Harigae, 2013). Recently, some new mutation genes and genetic sites were found along with the application of next-generation sequence technology, these findings facilitate people understanding the pathogenesis of CSA (An et al., 2015; Camaschella, 2009). However, because CSA is a relatively rare disease, the genetic and pathophysiologic features of CSA remain elusive.
Supported in part by Roche Foundation for Anemia Research (ROFAR).