A Novel Hemizygous I418S Mutation in the ALAS2 Gene in a Young Korean Man with X-Linked Sideroblastic Anemia

Dear Editor, Sideroblastic anemia is a heterogeneous disorder that is characterized by increased serum iron and ferritin levels, high number of hypochromic red blood cells (RBCs), and ineffective erythropoiesis with ringed sideroblasts in the bone marrow (BM) [1]. There are two forms of sideroblastic anemia: inherited and acquired. Acquired sideroblastic anemia usually develops because of alcohol consumption, toxin exposure, substance abuse, and myelodysplastic syndrome-refractory anemia with ring sideroblasts (MDS-RARS). Inherited sideroblastic anemia has a heterogeneous inheritance pattern including X-linked, autosomal, and mitochondrial entities. X-linked sideroblastic anemia (XLSA) is the most common type, constituting about 40% of inherited sideroblastic anemia [2]. Most cases of XLSA result from deficiency of delta-aminolevulinate synthase 2 (ALAS2), an erythroid-specific enzyme involved in the heme biosynthetic pathway. To date, more than 60 different mutations in the ALAS2 gene on the X chromosome of XLSA patients have been described [3]. Although several reports on inherited sideroblastic anemia in Korea have been published [4-6], the underlying genetic change, a well-known point mutation, was confirmed only in one case [4]. Since the morphologic findings of inherited sideroblastic anemia are usually similar to those of neoplastic MDSRARS, genetic analyses are useful in identifying inherited sideroblastic anemia. Here, we report a novel missense mutation of the ALAS2 gene in a young male patient presenting with severe sideroblastic anemia. A 27-yr-old man with a medical history of persistent severe anemia (at the age of 15) visited Seoul National University Hospital in November 2012. There was no family history of sideroblastic anemia. The initial complete blood count was as follows: Hb, 4.2 g/dL; Hct, 15.3%; erythrocytes, 3.16×10/L; mean corpuscular volume (MCV), 50.0 fL; mean corpuscular hemoglobin (MCH), 13.2 pg; mean corpuscular hemoglobin concentration (MCHC), 26.4 g/dL; red cell distribution width (RDW), 24.9%; reticulocytes, 0.2%; white blood cells, 6.15×10/L; and platelets, 530×10/L. The peripheral blood smear revealed a dimorphic red-cell population including normocytic, normochromic and microcytic, and hypochromic erythrocytes, along with severe anisopoikilocytosis (Fig. 1A). Tests for iron status indicated iron overload, with a serum iron level of 212 μg/dL, ferritin level of 641 ng/mL, and a total iron binding capacity of 249 μg/dL. Chromosome analysis, Hb electrophoresis, and flow cytometry analysis for cluster of differentiation (CD) 55 and CD59 did not indicate any abnormalities. BM study revealed marked erythroid hyperplasia (myeloid:erythroid ratio of 0.3:1) with mild dyseryth-