Congenital sideroblastic anemia: A report of two cases
ABSTRACT Sideroblastic anemia, comprising of acquired and congenital forms, is a heterogeneous group of disorders characterized by the presence of ring sideroblasts in the bone marrow. Congenital sideroblastic anemia is a rare condition which is mostly X-linked, caused by mutations of delta-aminolevulinic acid synthase 2. We describe two cases of congenital sideroblastic anemia, one of them indicating an autosomal recessive inheritance, with their clinico-hematological profile. It is important to recognize this entity early in life as a significant percentage of cases respond to pyridoxine thus avoiding any long-term complications.
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ABSTRACT: Sideroblastic anaemia includes a heterogeneous group of rare conditions, characterized by decreased haem synthesis and mitochondrial iron overload, which are diagnosed by the presence of ringed sideroblasts in the bone marrow aspirate. The most frequent form is X-linked sideroblastic anaemia, caused by mutations of delta-aminolevulinic acid synthase 2 (ALAS2), the enzyme that catalyses the first and regulatory step of haem synthesis in erythroid precursors and is post-transcriptionally controlled by the iron regulatory proteins. Impaired haem production causes variable degrees of anaemia and mitochondrial iron accumulation as ringed sideroblasts. The heterogeneity and complexity of sideroblastic anaemia is explained by an increasing number of recognized molecular defects. New forms have been recognized as being linked to the deficient function of mitochondrial proteins involved in iron-sulphur cluster biogenesis, such as ABCB7 and GLRX5, which are extremely rare but represent important biological models. Local mitochondrial iron overload is present in all sideroblastic anaemias, whereas systemic iron overload occurs only in the forms because of primary or secondary deficiency of ALAS2.British Journal of Haematology 10/2008; 143(1):27-38. DOI:10.1111/j.1365-2141.2008.07290.x · 4.96 Impact Factor
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ABSTRACT: X-linked sideroblastic anemia is usually associated with reduced 5-aminolevulinate synthase activity in erythroid cells, and some cases are responsive to treatment with pyridoxine, the precursor to the cofactor of the enzyme. The recently identified gene for an erythroid-specific 5-aminolevulinate synthase isoenzyme and its localization to the X chromosome make it likely that one or more defects in this gene underlie the anemia. Using a polymorphic dinucleotide-repeat sequence in the erythroid 5-aminolevulinate synthase gene, we confirmed the linkage of this gene to the disorder in a family with X-linked pyridoxine-responsive sideroblastic anemia. We therefore sought evidence of a nucleotide-sequence abnormality in the erythroid 5-aminolevulinate synthase gene by analyzing enzymatically amplified DNA. DNA-sequencing studies in two affected males and one carrier female in the kindred demonstrated a cytosine-to-guanine change at nucleotide 1215 (in exon 8). This change results in the substitution of serine for threonine at amino acid residue 388, near the lysine that binds the pyridoxal phosphate cofactor. In expression studies, the activity of the mutant enzyme was reduced relative to that of the wild type, and this reduction was comparable to that in erythroid cells of the proband during relapse of the anemia; the enzyme activity expressed in the presence of pyridoxine was comparable to that in the proband's marrow cells during remission. Although the affinity of the mutant enzyme for pyridoxal phosphate was not altered, the mutation appears to introduce a conformational change at the active site of the enzyme. We identified a point mutation resulting in an amino acid change near the pyridoxal phosphate-binding site of the erythroid 5-aminolevulinate synthase isoenzyme as the underlying defect in a kindred with X-linked pyridoxine-responsive sideroblastic anemia.New England Journal of Medicine 03/1994; 330(10):675-679. DOI:10.1056/NEJM199403103301004 · 54.42 Impact Factor
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ABSTRACT: 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.Seminars in Hematology 11/2002; 39(4):270-81. DOI:10.1053/shem.2002.35637 · 2.46 Impact Factor