Form Of Sideroblastic Anemia Research Articles

Causes and Pathophysiology of Acquired Sideroblastic Anemia.

The sideroblastic anemias are a heterogeneous group of inherited and acquired disorders characterized by anemia and the presence of ring sideroblasts in the bone marrow. Ring sideroblasts are abnormal erythroblasts with iron-loaded mitochondria that are visualized by Prussian blue staining as a perinuclear ring of green-blue granules. The mechanisms that lead to the ring sideroblast formation are heterogeneous, but in all of them, there is an abnormal deposition of iron in the mitochondria of erythroblasts. Congenital sideroblastic anemias include nonsyndromic and syndromic disorders. Acquired sideroblastic anemias include conditions that range from clonal disorders (myeloid neoplasms as myelodysplastic syndromes and myelodysplastic/myeloproliferative neoplasms with ring sideroblasts) to toxic or metabolic reversible sideroblastic anemia. In the last 30 years, due to the advances in genomic techniques, a deep knowledge of the pathophysiological mechanisms has been accomplished and the bases for possible targeted treatments have been established. The distinction between the different forms of sideroblastic anemia is based on the study of the characteristics of the anemia, age of diagnosis, clinical manifestations, and the performance of laboratory analysis involving genetic testing in many cases. This review focuses on the differential diagnosis of acquired disorders associated with ring sideroblasts.

When Ring Sideroblasts on Bone Marrow Smears Are Inconsistent with the Diagnosis of Myelodysplastic Neoplasms.

Ring sideroblasts are commonly seen in myelodysplastic neoplasms and are a key condition for identifying distinct entities of myelodysplastic neoplasms according to the WHO classification. However, the presence of ring sideroblasts is not exclusive to myelodysplastic neoplasms. Ring sideroblasts are as well either encountered in non-clonal secondary acquired disorders, such as exposure to toxic substances, drug/medicine, copper deficiency, zinc overload, lead poison, or hereditary sideroblastic anemias related to X-linked, autosomal, or mitochondrial mutations. This review article will discuss diseases associated with ring sideroblasts outside the context of myelodysplastic neoplasms. Knowledge of the differential diagnoses characterized by the presence of ring sideroblasts in bone marrow is essential to prevent any misdiagnosis, which leads to delayed diagnosis and subsequent management of patients that differ in the different forms of sideroblastic anemia.

Biology of sideroblastic anemia.

Sideroblastic anemia is characterized by anemia with ring sideroblasts produced by the bone marrow. Sideroblasts are formed by disutilization and deposit of iron in the mitochondoria. There are two forms of sideroblastic anemia: congenital and acquired. Congenital sideroblastic anemia is caused by mutations in genes involved in heme biosynthesis, iron-sulfur (Fe-S) cluster biogenesis, or mitochondrial metabolism. Although there is a variation in the mutated genes among races, the most common congenital sideroblastic anemia is X-linked sideroblastic anemia caused by mutations in the erythroid-specific δ-aminolevulinate synthase gene, which is the first enzyme of heme biosynthesis in erythroid cells. The most commonly acquired sideroblastic anemia is myelodysplastic syndrome with ring sideroblasts (MDS-RS). It has been shown that the splicing factor 3b subunit 1 (SF3B1) gene, which is a core component of the RNA splicing complex, is highly mutated in MDS-RS, although the underlying mechanism of the onset of the disease by the mutation of the SF3B1 gene remains unclear. Molecular analysis will contribute to the development of effective treatment for congenital and acquired sideroblastic anemia, which are intractable diseases.

Effects of GlyT1 inhibition on erythropoiesis and iron homeostasis in rats.

Glycine is a key rate-limiting component of heme biosynthesis in erythropoietic cells, where the high intracellular glycine demand is primarily supplied by the glycine transporter 1 (GlyT1). The impact of intracellular glycine restriction after GlyT1 inhibition on hematopoiesis and iron regulation is not well established. We investigated the effects of a potent and selective inhibitor of GlyT1, bitopertin, on erythropoiesis and iron homeostasis in rats. GlyT1 inhibition significantly affected erythroid heme biosynthesis, manifesting as microcytic hypochromic regenerative anemia with a 20% steady-state reduction in hemoglobin. Reduced erythropoietic iron utilization was characterized by down-regulation of the transferrin receptor 1 (TfR1) on reticulocytes and modest increased iron storage in the spleen. Hepatic hepcidin expression was not affected. However, under the condition of reduced heme biosynthesis with reduced iron reutilization and increased storage iron, hepcidin at the lower and higher range of normal showed a striking role in tissue distribution of iron. Rapid formation of iron-positive inclusion bodies (IBs) was observed in circulating reticulocytes, with an ultrastructure of iron-containing polymorphic mitochondrial remnants. IB or mitochondrial iron accumulation was absent in bone marrow erythroblasts. In conclusion, GlyT1 inhibition in rats induced a steady-state microcytic hypochromic regenerative anemia and a species-specific accumulation of uncommitted mitochondrial iron in reticulocytes. Importantly, this glycine-restricted anemia provides no feedback signal for increased systemic iron acquisition and the effects reported are pathogenetically distinct from systemic iron-overload anemias and erythropoietic disorders such as acquired sideroblastic anemia.

Clinical and genetic characteristics of congenital sideroblastic anemia: comparison with myelodysplastic syndrome with ring sideroblast (MDS-RS)

Sideroblastic anemia is characterized by anemia with the emergence of ring sideroblasts in the bone marrow. There are two forms of sideroblastic anemia, i.e., congenital sideroblastic anemia (CSA) and acquired sideroblastic anemia. In order to clarify the pathophysiology of sideroblastic anemia, a nationwide survey consisting of clinical and molecular genetic analysis was performed in Japan. As of January 31, 2012, data of 137 cases of sideroblastic anemia, including 72 cases of myelodysplastic syndrome (MDS)–refractory cytopenia with multilineage dysplasia (RCMD), 47 cases of MDS–refractory anemia with ring sideroblasts (RARS), and 18 cases of CSA, have been collected. Hemoglobin and MCV level in CSA are significantly lower than those of MDS, whereas serum iron level in CSA is significantly higher than those of MDS. Of 14 CSA for which DNA was available for genetic analysis, 10 cases were diagnosed as X-linked sideroblastic anemia due to ALAS2 gene mutation. The mutation of SF3B1 gene, which was frequently mutated in MDS-RS, was not detected in CSA patients. Together with the difference of clinical data, it is suggested that genetic background, which is responsible for the development of CSA, is different from that of MDS-RS.Electronic supplementary materialThe online version of this article (doi:10.1007/s00277-012-1564-5) contains supplementary material, which is available to authorized users.

Epidemiological and Genetic Analysis of Sideroblastic Anemia — Multicenter Study In Japan

AbstractAbstract 4225 Introduction:Sideroblastic anemia is characterized by anemia with the emergence of ring sideroblasts in the bone marrow. There are two forms of sideroblastic anemia. One is an inherited sideroblastic anemia, and another is an acquired sideroblastic anemia. Because sideroblastic anemia is a rare disease, there are few comprehensive studies of sideroblastic anemia, including clinical and genetic information. In the present study, we have performed national-wide survey of sideroblastic anemia in Japan to investigate the epidemiology and pathogenesis of the disease. Method:This study consists of three-step surveys. First, the patients of sideroblastic anemia were searched by simple questionnaire to hematological department of hospitals in all areas in Japan (first investigation). Next, detailed clinical information of sideroblastic anemia patients were collected (second investigation). Survey items were age of onset, gender, family history, hematology, bone marrow and biochemical findings. Then, genetic analyses of patients who were suspected inherited sideroblastic anemia were performed (third investigation). For the genetic analysis, mutations of ALAS2, ABC7, GLRX5, SLC25A38, which are known to be responsible genes for inherited sideroblastic anemia, were examined. Result: At the first investigation, sideroblastic anemia patients were surveyed in the 1086 institutions of Japan. There were 14 cases of confirmed or suspected cases of inherited sideroblastic anemia and 285 cases of suspected or confirmed cases of acquired sideroblastic anemia. These patients were subjects of second investigation. As of August 9, data of 99 patients have been collected. In these cases there are 7 cases of confirmed inherited sideroblastic anemia, 7 cases of suspected inherited sideroblastic anemia, 28 cases of refractory anemia with ring sideroblasts (MDS-RARS) and 57 cases of refractory cytopenia with multilineage dysplasia with ring sideroblasts (MDS-RCMD-RS). Median age of onset was 70.5 years old in MDS-RCMD-RS cases, whereas that of cases in inherited sideroblastic anemia was 14 years old. Hemoglobin level in inherited sideroblastic anemia and RCMD-RS was 6.7g/dl and 8.3g/dl. MCV was 64.7 fl, 105.1 fl in inherited sideroblastic anemia and RCMD-RS. There was thus significant different between MCV level in inherited sideroblastic anemia and RCMD-RS. Chromosomal abnormality of +8 and idic (X) (q13), associated with ABC7 gene, were detected in 7 and 2 of 25 RCMD-RS patients, respectively. At the moment, 4 confirmed and 4 suspected patients of inherited sideroblastic anemia proceeded to third investigation. As a result, mutations of ALAS2, which is the first enzyme of heme biosynthesis in erythroid cells, have been identified in 6 out of 8 patients. The amino acid mutations were detected in exon 5 (R170C, R170L), exon 9 (R411C, R452C), and exon 11 (V562A). For patients without mutations in ALAS2 gene, mutations of other genes related to inherited sideroblastic anemia have been analyzed; however, no mutations are identified so far. Conclusion: The results showed that RCMD-RS is most common in sideroblastic anemia, and XLSA is most frequent type of inherited sideroblastic anemia. However, there are significant number of suspected cases of inherited sideroblastic anemia. The genetic analysis of these cases, including RARS without chromosomal anomaly, is currently in progress. This research has been supported by Grant-in-Aid for Scientific Research from Ministry of Health, Labour and Welfare of Japan. Disclosures:No relevant conflicts of interest to declare.

Hereditary sideroblastic anemia: pathophysiology and gene mutations

Sideroblastic anemia is characterized by anemia with the emergence of ring sideroblasts in the bone marrow. Ring sideroblasts are erythroblasts characterized by iron accumulation in perinuclear mitochondria due to impaired iron utilization. There are two forms of sideroblastic anemia, i.e., inherited and acquired sideroblastic anemia. Inherited sideroblastic anemia is a rare and heterogeneous disease caused by mutations of genes involved in heme biosynthesis, iron-sulfur (Fe-S) cluster biogenesis, or Fe-S cluster transport, and mitochondrial metabolism. The most common inherited sideroblastic anemia is X-linked sideroblastic anemia (XLSA) caused by mutations of the erythroid-specific δ-aminolevulinate synthase gene (ALAS2), which is the first enzyme of heme biosynthesis in erythroid cells. Sideroblastic anemia due to SLC25A38 gene mutations, which is a mitochondrial transporter, is the next most common inherited sideroblastic anemia. Other forms of inherited sideroblastic anemia are very rare, and accompanied by impaired function of organs other than hematopoietic tissue, such as the nervous system, muscle, or exocrine glands due to impaired mitochondrial metabolism. Moreover, there are still significant numbers of cases with genetically undefined inherited sideroblastic anemia. Molecular analysis of these cases will contribute not only to the development of effective treatment, but also to the understanding of mitochondrial iron metabolism.

Pyridoxal-5-Phosphate-Resistant Sideroblastic Anaemia with Trisomy 8 Mosaicism in the Bone Marrow

A patient with sideroblastic anaemia manifested a trisomic condition for chromosome number 8 in 75% of his bone marrow cells. Cytogenetic studies of peripheral lymphocytes demonstrated a normal male karyotype. The anaemia was resistant to treatment with pyridoxal-5-phosphate; this is in contradiction with the response achieved in some patients with the primary acquired form of sideroblastic anaemia.