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

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.

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.

No relevant conflicts of interest to declare.