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At least 19 recordsLinked to original sources
PubMed2006

[Sideroblastic anemias].

Sideroblastic anemias are a heterogenous group of disorders characterized by the presence of sideroblasts in the bone marrow aspirate. Current classification schemes distinguish between diseases of the heme synthesis pathway and diseases of other mitochondrial pathways which can either be of primary origin (defects in mitochondrial DNA) or of secondary origin (defects in nuclear DNA). Although several distinct hereditary forms exist, sideroblastic anemias are most frequently acquired diseases and belong to the group of myelodysplastic syndromes with the propensity to develop into overt leukemia. Treatment is mainly supportive (vitamins, blood transfusions, cytokines) and only rarely are bone marrow transplantations performed. The molecular defects of a few hereditary forms have already been elucidated, but the genes involved in the acquired forms are still largely unknown.

Anemia, Sideroblastic↗
PubMed1992

Successive pregnancies complicated by idiopathic sideroblastic anemia.

Sideroblastic anemias are a diverse group of hypoproliferative anemias characterized by defective iron use within erythropoietic cells and a defect in heme biosynthesis. This report describes the first case of successive pregnancies in a patient with idiopathic sideroblastic anemia. Periodic transfusions with washed erythrocytes and oral pyridoxine resulted in normal maternal and perinatal outcome.

Adult↗
PubMed1998

Sideroblastic anemias: variations on imprecision in diagnostic criteria, proposal for an extended classification of sideroblastic anemias.

Sideroblastic anemias are caused by a diversity of hereditary, congenital, or acquired disorders. Criteria used in describing sideroblastic anemias vary widely among standard medical textbooks and even so have been imprecisely applied in the literature. Recent discoveries concerning the basic pathophysiologic mechanisms involving the molecular biology of nuclear and mitochondrial DNA, erythroid ALA synthase (ALAS-2), and iron transport have made the classification of sideroblastic anemias very complex. We recommend a more precise evaluation and documentation of the components that characterize the sideroblastic abnormality and propose an extended classification of the sideroblastic anemias.

5-Aminolevulinate Synthetase↗
PubMed2006

Candidate gene mutation analysis in idiopathic acquired sideroblastic anemia (refractory anemia with ringed sideroblasts).

BACKGROUND: For most cases of idiopathic acquired sideroblastic anemia (IASA), the molecular pathogenesis is unknown, despite the consistent morphological signature of abundant pathological ringed sideroblasts with their characteristic iron-engorged mitochondria. Moderately elevated free erythrocyte protoporphyrin (FEP) levels have been described in IASA, suggesting that the activity of ferrochelatase, the enzyme that catalyzes the final step in heme biosynthesis (incorporation of ferrous iron into protoporphyrin), might be diminished in erythroid progenitor cells from IASA patients. METHODS: We confirmed FEP elevation in IASA, then pursued a candidate gene approach that included screening the gene encoding ferrochelatase, FECH, for promoter and coding region mutations and mRNA expression changes in bone marrow from 37 patients with IASA. RESULTS: The analytical techniques employed detected mutations in a test cohort of previously undiagnosed patients with biochemical evidence for erythropoietic protoporphyria, a condition resulting from germline mutations in FECH, but somatic missense mutations of FECH and its promoter were not observed in IASA patients. FECH was modestly overexpressed in progenitor cells from patients with IASA, compared with MDS patients without sideroblasts and healthy controls. In addition, we analyzed ABCB7 and PUS1, genes implicated in congenital sideroblastic anemia syndromes, but again found no coding mutations in acquired cases. CONCLUSION: We conclude that acquired mutations in the factors currently known to cause inherited sideroblastic anemias are uncommon in IASA.

ATP-Binding Cassette Transporters↗
PubMed1995

Late-onset X-linked sideroblastic anemia. Missense mutations in the erythroid delta-aminolevulinate synthase (ALAS2) gene in two pyridoxine-responsive patients initially diagnosed with acquired refractory anemia and ringed sideroblasts.

X-linked sideroblastic anemia (XLSA) is caused by mutations of the erythroid-specific delta-aminolevulinate synthase gene (ALAS2) resulting in deficient heme synthesis. The characteristic hypochromic, microcytic anemia typically becomes manifest in the first three decades of life. Hematologic response to pyridoxine is variable and rarely complete. We report two unrelated cases of highly pyridoxine-responsive XLSA in geriatric patients previously diagnosed with refractory anemia and ringed sideroblasts. A previously unaffected 77-yr-old male and an 81-yr-old female were each found to have developed severe hypochromic, microcytic anemia with ringed sideroblasts in the bone marrow, which responded dramatically to pyridoxine with normalization of hemoglobin values. Sequence analysis identified an A to C transversion in exon 7 (K299Q) of the ALAS2 gene in the male proband and his daughter. In the female proband a G to A transition was identified in exon 5 (A172T). This mutation resulted in decreased in vitro stability of bone marrow delta-aminolevulinate synthase activity. Each patient's recombinant mutant ALAS2 enzyme had marked thermolability. Addition of pyridoxal 5'-phosphate in vitro stabilized the mutant enzymes, consistent with the observed dramatic response to pyridoxine in vivo. This late-onset form of XLSA can be distinguished from refractory anemia and ringed sideroblasts by microcytosis, pyridoxine-responsiveness, and ALAS2 mutations. These findings emphasize the need to consider all elderly patients with microcytic sideroblastic anemia as candidates for XLSA, especially if pyridoxine responsiveness is demonstrated.

5-Aminolevulinate Synthetase↗
PubMed1979

Idiopathic sideroblastic anemia: presence of sideroblastic changes in the erythropoietic precursors cultured from peripheral blood.

Peripheral blood mononuclear cells from five patients with idiopathic sideroblastic anemia were examined in clonal culture for circulating erythropoietic precursors. Three of these patients had relatively mild anemia and revealed significant burst formation. Two patients who had severe anemia and required regular blood transfusions showed severe diminution or absence of circulating precursors. These results could suggest that the number of circulating erythropoietic precursors reflects effective erythropoiesis in the marrow. Ultrastructural morphology and ultrastructural Prussian-blue staining of the bursts from a patient revealed the characteristic mitochondrial deposition of ferrugionous material in pathologic normoblasts. Peripheral blood clonal cell cultures would, therefore, appear to be a potentially useful tool for analysis of biochemical abnormalities in idiopathic sideroblastic anemia.

Aged↗
PubMed2002

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.

Anemia, Sideroblastic↗
PubMed2002

Mitochondrial ferritin expression in erythroid cells from patients with sideroblastic anemia.

The sideroblastic anemias are characterized by ring sideroblasts, that is, red cell precursors with mitochondrial iron accumulation. We therefore studied the expression of mitochondrial ferritin (MtF) in these conditions. Erythroid cells from 13 patients with refractory anemia with ring sideroblasts (RARS) and 3 patients with X-linked sideroblastic anemia (XLSA) were analyzed for the distribution of cytoplasmic H ferritin (HF) and MtF using immunocytochemical methods. We also studied 11 healthy controls, 5 patients with refractory anemia without ring sideroblasts (RA), and 7 patients with RA with excess of blasts (RAEB). About one fourth of normal immature red cells, mostly proerythroblasts and basophilic erythroblasts, showed diffuse cytoplasmic positivity for HF, but very few were positive for MtF (0%-10%). Similar patterns were found in anemic patients without ring sideroblasts. In contrast, many erythroblasts from patients with sideroblastic anemia (82%-90% in XLSA and 36%-84% in RARS) were positive for MtF, which regularly appeared as granules ringing the nucleus. Double immunocytochemical staining confirmed the different cellular distribution of HF and MtF. There was a highly significant relationship between the percentage of MtF(+) erythroblasts and that of ring sideroblasts (Spearman R = 0.90; P <.0001). Reverse transcription-polymerase chain reaction studies demonstrated the presence of MtF mRNA in circulating reticulocytes of 2 patients with XLSA but not in controls. These findings suggest that most of the iron deposited in perinuclear mitochondria of ring sideroblasts is present in the form of MtF and that this latter might be a specific marker of sideroblastic anemia.

5-Aminolevulinate Synthetase↗
PubMed2003

Nonmyeloablative allogeneic hematopoietic stem cell transplantation for congenital sideroblastic anemia.

Congenital sideroblastic anemia (CSA) is a dyserythropoietic disorder that leads to transfusion dependency and subsequent iron overload. Nonmyeloablative allogeneic hematopoietic stem cell transplantation (NST) was performed for a patient with CSA, who had contraindications to conventional allografting. Conditioning was fludarabine, low-dose total body irradiation and antithymocyte globulin, followed by peripheral blood stem cell transplant. Cyclosporine and mycophenolate mofetil were used for graft-versus-host disease prophylaxis. Complete donor chimerism was observed day +131. Early after transplant, the patient became transfusion independent, allowing a regular phlebotomy program. On day +190, refractory lactic acidosis followed by fatal cardiovascular collapse developed, without evidence of infection. Data from this case demonstrates that NST may correct the erythropoietic defect of CSA.

Adult↗
PubMed1996

The molecular basis of the sideroblastic anemias.

The sideroblastic anemias display remarkable clinical and hematologic heterogeneity but share in common mitochondrial iron loading as evidence of unhinging between intracellular iron metabolism and heme biosynthesis. Molecular defects responsible for this unhinging have now been identified and appear to display matching heterogeneity. Mutations in the erythroid-specific ALA synthase 2 (ALAS2) gene cause microcytic anemia, whereas mitochondrial DNA deletions are responsible for Pearsons syndrome with a macrocytic anemia. The molecular basis for other causes including X-linked non-ALAS2-associated autosomal inheritance and for the more frequent acquired forms of this disorder awaits discovery. Speculation about their causes includes disturbed intracellular iron homeostasis involving iron-responsive factors involved in the translational control of ALAS2 and in certain nuclear and mitochondrial genes important for erythroid mitochondrial metabolism.

5-Aminolevulinate Synthetase↗
PubMed2002

Multiple mechanisms for hereditary sideroblastic anemia.

Hereditary sideroblastic anemia (HSA) is a heterogeneous group of inherited anemic disorders which is characterized by the presence of ringed sideroblasts in the bone marrow, microcytic hypochromic anemia and typically its X-linked inheritance in patients. It has been shown that a deficiency of the erythroid-specific delta-aminolevulinate synthase (ALAS-E) activity is responsible for pyridoxine-responsive HSA in many patients, however, the pathogenesis of other types of HSA remains still unknown. In this article, recent evidence suggesting multiple causes for HSA is summarized and discussed.

5-Aminolevulinate Synthetase↗
PubMed1995

Phosphaturia, glycosuria and aminoaciduria associated with idiopathic acquired sideroblastic anemia.

Idiopathic acquired sideroblastic anemia is not a common disease. We studied the renal tubular function in such patients. Patients have lower calcium than controls (8.46 mg/dl +/- 0.59 vs 9.16 +/- 0.53). We have highlighted the multiple renal anomalies observed in patients with this type of hemopathy. The serum phosphate levels are lower in patients than in controls (2.73 +/- 0.36 vs 3.3 +/- 0.55 mg/dl, p = 0.0048). We found higher glycosuria (21:43 +/- 42.58 vs 0.0 +/- 0.0 mg/dl), total aminoaciduria (6280 +/- 3943 vs 4138 +/- 2269 microMol/g creatinine, p = 0.19) and lower maximum capacity for phosphate reabsorption by the renal tube (TmPO4) (2.11 +/- 0.38 vs 2.9 +/- 0.73 mg/100 ml GFR, p = 0.0027) in the patients. The association between idiopathic acquired sideroblastic anemia and the multiple tubular anomalies corresponding to the syndrome initially described by Fanconi has not been reported to date. The underlying mechanism is not understood, but, taken separately, these two anomalies commonly present heme metabolic anomalies in the mitochondria. We hypothesize that this syndrome could represent the clinical expression of a mitochondrial cytopathology.

Aged↗
PubMed2006

Congenital sideroblastic anemias.

Congenital forms of sideroblastic anemia constitute a subset of uncommon disorders within the wider spectrum of sideroblastic anemias, all of which are diagnosed by the presence of pathologic iron deposits in erythroblast mitochondria. The congenital sideroblastic anemias are heterogeneous disorders; some arise from known molecular defects but others are diagnosed only by their clinical features. Elucidation of several of the underlying defects has advanced our understanding of heme biosynthesis and iron metabolism in the erythroid cell. With the details of the porphyrin synthetic pathway clarified, now the important frontier of research is investigation of the mechanisms of mitochondrial and cellular iron homeostasis and their relationship to the regulation of heme biosynthesis. Knowledge gained from efforts in this area of study may also provide new approaches to treatments, which remain largely supportive for most types of congenital sideroblastic anemia.

Anemia, Sideroblastic↗
PubMed1984

[Refractory and sideroblastic anemias].

Refractory and sideroblastic anemias are heterogenous syndromes which are characterized by a hyperblastic bone marrow with dyserythropoietic features and disturbances in iron- and hemoglobin metabolism. Various pathogenetic and therapeutic aspects as well as connections with the preleukemic syndromes are discussed.

Anemia, Hypochromic↗
PubMed1991

[Sideroblastic anemias].

The sideroblastic anaemias form a group of disorders of varying aetiology. They are being recognized with increasing frequency, especially as routine staining of bone marrow films for iron is now standard practice in most foreign laboratories. The sideroblastic anaemias have as a common feature the presence of large numbers of pathologic (ringed) sideroblasts in the bone marrow, ineffective erythropoiesis, a high degree of saturation of serum transferrin, increased levels of tissue iron and varying proportions of hypochromic erythrocytes in the peripheral blood. The marrow structure often exhibits dyserythropoietic features. Special attention has been focused by the authors upon the diagnostic and differential diagnostic problems, the ferrokinetics, the preleukemic condition and the therapeutics measures now available. There is also possible to draw some utilizable conclusions from the experiences of the authors.

Aged↗