Late-onset X-linked sideroblastic anemia following hemodialysis

Abstract

X-linked sideroblastic anemia (XLSA) is due to deficient activity of erythroidspecific 5-aminolevulinate synthase (ALAS2). We report here a patient who developed sideroblastic anemia at the age of 81 years while undergoing hemodialysis. The diagnosis of sideroblastic anemia was established by the presence of ringed sideroblasts in the bone marrow, and treatment with oral pyridoxine completely eliminated the ringed sideroblasts. We identified a novel point mutation in the fifth exon of this patient's ALAS2 gene, which resulted in an amino acid change at residue 159 from aspartic acid to asparagine (Asp159Asn IntroductionX-linked sideroblastic anemia (XLSA) is an X-linked recessive hypochromic, microcytic anemia with ringed sideroblasts in the bone marrow, resulting from the deficient activity of erythroidspecific 5-aminolevulinate synthase (ALAS2, or ALAS-E; EC 2.3.1.37). XLSA typically presents by the fourth decade of life, however, there are rare cases that may manifest later in life. Late-onset XLSA merits special mention not only because it is extremely rare (only 3 cases have been reported), but also because there has been no direct evidence that the mutations of ALAS2 resulted in the disease. [1][2][3] In this study, we report a patient with late-onset XLSA who developed the disease following hemodialysis. The diagnosis was confirmed by molecular analysis of the ALAS2 gene. Study design Case reportAn 81-year-old male patient was admitted to Kyoto Minute-I-Ren Central Hospital in September 2000, with the diagnosis of chronic renal failure and sideroblastic anemia. Prior to admission, he had been treated with hemodialysis for 2 1/2 years. Erythropoietin was administered (3000 U subcutaneously 3 times weekly), yet he remained anemic (red blood cell , 4.6 ϫ 10 9 /L) with an increased red cell distribution width of 19.8% (normal, 11.6%-15.0%). The peripheral blood smear revealed both normocytic and microcytic erythrocyte populations. The MCV dropped to 82.4 fL before additional packed red cell transfusions were administered. A bone marrow examination revealed a hypocellular marrow with a normal myeloid-erythroid ratio. Prussian blue staining of bone marrow cells revealed the presence of numerous ringed sideroblasts (49% of the erythroblasts). The serum ferritin concentration was elevated at 797 g/L. A myelodysplastic syndrome was suspected, namely refractory anemia with ringed sideroblasts (RARS) and additional packed red cell transfusions were administered. A serum pyridoxal level was less than 2.0 ng/mL (normal, 6.0-40.0 ng/mL) and oral pyridoxine (200 mg/d) was started. After 2 weeks of pyridoxine therapy, the anemia stabilized and no further transfusions were required. The bone marrow examination was repeated and ringed sideroblasts were no longer evident. Hemoglobin levels were maintained at or higher than 70 g/L with continued pyridoxine treatment, but the patient died of aspiration pneumonia in November 2000. Identification of an ALAS2 mutationAn autopsy sample of the patient's liver, which had been stor...

Abcb10 Role in Heme Biosynthesis In Vivo: Abcb10 Knockout in Mice Causes Anemia with Protoporphyrin IX and Iron Accumulation

“…However, there have been no reports showing abnormalities in ABCB10 in human SA and EPP (28,29). This discrepancy between our finding and the results of human genetic analysis can be explained by the complex combination of genetic abnormalities and/or the difficulty of genetic and epidemiologic analysis of SA because of its rarity and the variety of symptoms and severities caused by the disease (30,31). Crossbreeding of Abcb10 heterozygous deletion mice with KO mice carrying other heme synthesisrelated genes may provide important clues regarding the genetic background of heme synthesis abnormalities.…”

Renal manifestations of primary mitochondrial disorders

“…In an infant with primary coenzyme-Q deficiency due to a mutation in the COQ2 gene, the MID manifested with nephrotic syndrome due to FSGS (51). In an 81-year-old male with XLSA due to mutations in the ALAS2 gene, renal involvement manifested as severe renal failure requiring haemodialysis (47). In a study of four patients with Leigh syndrome due to a mutation in the SURF1 gene, three had significant proximal RTA (48).…”

Heme as a Magnificent Molecule with Multiple Missions: Heme Determines Its Own Fate and Governs Cellular Homeostasis

“…For this purpose, intravenous administration of heme (as hematin, heme arginate or heme albumin), in addition to general and supportive care, is usually selected as a first-line therapy for the treatment of acute attacks of porphyria (Anderson et al 2001). While the human disease caused by the mutation of ALAS1 gene has never been reported, it is well known that the genetic mutation of ALAS2 gene causes X-linked sideroblastic anemia (XLSA) (Cotter et al 1992b;Cox et al 1994;Furuyama et al 1997Furuyama et al , 1998Furuyama et al , 2003Furuyama et al , 2006May and Bishop 1998;Harigae et al 1999a, b;Furuyama and Sassa 2002). In addition to X-linked inheritance of the anemia, XLSA is characterized by the presence of ringed sideroblasts in bone marrow (Anderson et al 2001).…”