Primary Sideroblastic Anaemia Research Articles

ATP-Binding Cassette Transporter of Clinical Significance: Sideroblastic Anemia.

The ATP-binding cassette (ABC) transporters are a vast group of 48 membrane proteins, some of which are of notable physiological and clinical importance. Some ABC transporters are involved in functions such as the transport of chloride ions, bilirubin, reproductive hormones, cholesterol, and iron. Consequently, genetic or physiological disruption in these functions is manifested in various disease processes like cystic fibrosis, Tangier disease, and sideroblastic anemia. Among other etiologies, primary sideroblastic anemia results from a genetic mutation in the ATP-binding cassette-7 (ABCB7), a member of the ABC transporter family. There are not many articles specifically tackling the disease processes caused by ABC transporters in detail. Some testing methodologies previously reported in the available literature for investigating sideroblastic anemia need updating. Here, we expound on the relevance of ABCB7 as a clinically important ABC transporter and a rare participant in the disease process of Sideroblastic anemia. The other genetic and secondary etiologies of sideroblastic anemia, which do not involve mutations in the ABCB7 protein, are also described. We review the pathophysiology, clinical course, symptoms, diagnosis, and treatment of sideroblastic anemia with a focus on modern technologies for laboratory testing.

Oxidatively Modified Serotransferrin in Refractory Anemia with Ring Sideroblasts

IntroductionRefractory anemia with ring sideroblasts (RARS), as a form of acquired primary sideroblastic anemia, represents about 11% of myelodysplastic syndromes (MDS) and is classified as a low risk MDS. It´s defined by the WHO as a pure dyserythropoietic disorder with presence of >15% ringed sideroblasts in the bone marrow. Abnormal expression of several genes of heme synthesis in this MDS subgroup and excessive accumulation of iron especially in mitochondria, the main place of reactive oxygen species (ROS) formation, contributes to the elevated oxidative stress. Oxidative stress is also known as one of the factors involved in the pathogenesis of MDS. High iron concentrations catalyse a Fenton reaction, where a hydroxyl radical is produced from hydrogen peroxide and causes an increase in ROS which may lead to the oxidation of DNA, lipids, and proteins, thereby causing cell damage.The aim of this study was to find a useful method for detection and identification of oxidatively modified proteins in plasma unique for RARS patients.MethodsCarbonylated protein levels were determined spectrophotometrically using dinitrophenylhydrazine (DNPH) derivatization. Oxidatively modified proteins of plasma samples were derivatized with biotin hydrazide. The dialyzed biotin hydrazide labeled samples and negative controls were mixed with monomeric avidin resin. Captured carbonylated proteins were digested by trypsin and then identified by MS/MS mass spectrometry coupled to a nano-LC system. Mascot (Matrix Science, London, UK) was used for database searching (Swiss-Prot). Two unique peptides (with a higher Mascot score than the minimum for identification, P<0.05) were necessary to successfully identify a protein.Serum iron (Fe), serum ferritin, transferrin, total iron binding capacity (TIBC), and iron saturation were estimated in MDS patients in the Central National Biochemical Laboratory at the Institute of Hematology and Blood Transfusion.ResultsWe have compared plasma of RARS patients with healthy controls or with RCMD patients. We have found significant differences in the measured carbonyl levels between all three groups (***P=0.00036). Furthermore, carbonylated protein levels were significantly elevated in RARS patients (n=10; 2.63±0.58 nmol/mg protein) compared to healthy donors (n=20; 1.80±0.42 nmol/mg protein) (***P<0.001) and to RCMD patients (n=10; 1.83±0.58 nmol/mg protein) (**P=0.00298). We have identified a total number of 27 carbonylated proteins unique for RARS patients which were generated by the effect of ROS. Serotransferrin was found as one of the oxidatively modified proteins. We have also found a significant decrease in TIBC in RARS patients compared to RCMD patients (*P=0.03078). TIBC moderately negatively correlated with carbonyl levels (r=-0.56, P=0.04864) in two investigated subgroups of MDS.ConclusionsWe have shown that there is a clear difference in the effect of oxidative stress between RARS, RCMD patients and healthy controls. Moreover, RARS patients, as a low risk MDS, are characterized by significantly higher protein carbonyl levels in comparison to healthy controls and to RCMD patients. The various sensibility of proteins to oxidation (carbonylation) depends both on their plasma concentration and on their susceptibility to oxidative stress as metal-binding sites or structural characteristics of the proteins. Modification in molecular structure of transferrin could be associated with decreased TIBC. This is in agreement with our data of oxidative modification of serotransferrin in RARS patients and could explain the decreased TIBC levels. Our results suggest that measurement of plasma carbonyl levels and the isolation and identification of carbonylated plasma proteins could serve as a potential diagnostic and prognostic tool in MDS.AcknowledgmentThis work was supported by the project of the Ministry of Health of the Czech Republic for conceptual development of the research organization 00023736, by Grant from the Academy of Sciences, Czech Republic (P205/12/G118), and by ERDF OPPK CZ.2.16/3.1.00/28007. DisclosuresNo relevant conflicts of interest to declare.

A-10. 鉄芽球性貧血における骨髄赤芽球δ-アミノレブリン酸合成酵素の特異性

A-10. 鉄芽球性貧血における骨髄赤芽球δ-アミノレブリン酸合成酵素の特異性

Erythrocyte ferritin in normal subjects and patients with abnormal iron metabolism.

Summary. Erythrocyte ferritin is about 10 times more reactive with antibody to heart ferritin than to spleen ferritin. The concentration of erythrocyte ferritin reflects the abnormal body iron status both in iron deficiency and in idiopathic haemochromatosis. Increased concentrations in β‐thalassaemia trait and primary sideroblastic anaemia may also reflect the intrinsic erythroid abnormality. Differences in the response of ‘heart‐type’ and ‘spleen‐type’ ferritin to changes of iron status suggest possible differences in metabolic function.

Erythroblast iron metabolism in sideroblastic marrows.

The uptake of iron by bone marrow erythroblasts and its intracellular distribution have been studied in 23 patients with primary sideroblastic anaemia (SA), five patients with secondary SA and one patient with only non-ringed sideroblasts. EM of erythroblasts from 18 cases showed both mitochondrial iron deposits and cytoplasmic ferritin aggregates in all cases except the patient with only non-ringed sideroblasts. Iron uptake by erythroblasts in whole bone marrow was normal but there was a decreased incorporation into haem and an increased incorporation into cell stroma. Age matching of erythroblasts using Percoll density gradient centrifugation indicated that stromal iron incorporation was high at all stages of erythroblast development even before haem synthesis had become a major metabolic activity and in intermediate and late erythroblasts a real decrease in haem synthesis appeared less certain. These observations, together with the inability to correct the abnormality in vitro with either pyridoxal phosphate or delta amino-laevulinic acid suggest that the primary defect in SA may be an abnormality of mitochondrial iron metabolism rather than an abnormality of haem synthesis.

Pyridoxine‐Responsive Primary Acquired Sideroblastic Anaemia

The activity of 5-aminolaevulinate (ALA) synthase, the first and rate-limiting of haem synthesis, was markedly reduced (13% of controls) in erythroblasts of a patient with acquired, primary sideroblastic anaemia (PASA). The reduced activity of ALA synthase could not be restored in vitro with 1 mmol/l pyridoxal-5-phosphate (PLP). Treatment of the patient with pyridoxine for several months increased the ALA synthase activity from 13% to 50% of controls in the absence and to 100% in the presence of PLP in the incubation medium. These studies suggest that both increased degradation of apo-ALA synthase and decreased affinity of ALA synthase for PLP may be involved in pyridoxine-responsive PASA.

The response of a child with primary sideroblastic anemia to cyclophosphamide [letter

The response of a child with primary sideroblastic anemia to cyclophosphamide [letter

Sideroblastic Anemia Treated With Immunosuppressive Therapy

Abstract A case of apparently primary sideroblastic anemia, in an elderly woman, refractory to hematinic therapy and requiring many blood transfusions, was treated with azathioprine. Over a period of 6 mo, the hemoglobin level gradually rose to normal, no further transfusions have been required in the 30 mo since then, and the marrow picture shows a considerable decrease in the degree of mitochondrial iron overload. There was a simultaneous fall in the titer of HL-A cytotoxic antibodies. The possible role of immunologic factors in this sequence of events is discussed.

Primary acquired sideroblastic anaemia: response to treatment with pyridoxal-5-phosphate.

A 72-year-old woman with primary sideroblastic anaemia showed no response to treatment with pyridoxine. When she was given pyridoxal-5-phosphate there was a prompt reticulocyte response and sustained symptomatic improvement with satisfactory control of the anaemia.

Acquired Primary Sideroblastic Anemia&mdash;A Report of Four Cases.

Acquired Primary Sideroblastic Anemia&mdash;A Report of Four Cases.

Heme Synthesis in Erythroblasts of Patients with Primary Sideroblastic Anemia.

Heme Synthesis in Erythroblasts of Patients with Primary Sideroblastic Anemia.

A Case of Acquired Primary Sideroblastic Anemia

A Case of Acquired Primary Sideroblastic Anemia