Sideroblastic anemia, iron overload, and ALAS2 R452S in African-American males: phenotype and genotype features of five unrelated patients
AMERICAN JOURNAL OF HEMATOLOGY
Authors: Lee, Pauline L.; Reid, Thomas J., III; Bottomley, Sylvia S.; Barton, James C.
Abstract
There are few reports of X-linked sideroblastic anemia (XLSA), iron overload, and mutations in ALAS2 that encodes 5-aminolevulinate synthase 2 in persons of sub-Saharan African Native descent [1-3]. A 50-year-old African-American man presented with microcytic anemia and mild thrombocytopenia. He had sideroblastic anemia, severe iron overload, cirrhosis, mild cardiomyopathy, diabetes mellitus, and antiplatelet antibodies. He was hemizygous for ALAS2 R452S (exon 9; c. 1406C -> A) and heterozygous for HFE H63D, but had no coding region mutations in TFR2, HAMP, HJV, or SLC40A1. Specific activity of the R452S protein was 80% of that of the normal recombinant enzyme. Its kinetic characteristics did not differ from those of the wild-type protein. We identified four other probands with sideroblastic anemia and ALAS2 R452S; all were African-American males. The five individuals appear phenotypically homogeneous, presenting with moderate anemia; the four adults presented with iron overload. This report updates the occurrence of XLSA among race/ethnicity groups, and raises the possibility that ALAS2 R452S occurs only in persons of sub-Saharan African Native descent.
Mutations in the HFE, TFR2, and SLC40A1 genes in patients with hemochromatosis
GENE
Authors: del-Castillo-Rueda, Alejandro; Moreno-Carralero, Maria-Isabel; Cuadrado-Grande, Nuria; Alvarez-Sala-Walther, Luis-Antonio; Enriquez-de-Salamanca, Rafael; Mendez, Manuel; Moran-Jimenez, Maria-Josefa
Abstract
Hereditary hemochromatosis causes iron overload and is associated with a variety of genetic and phenotypic conditions. Early diagnosis is important so that effective treatment can be administered and the risk of tissue damage avoided. Most patients are homozygous for the c845G>A (p.C282Y) mutation in the HFE gene; however, rare forms of genetic iron overload must be diagnosed using a specific genetic analysis. We studied the genotype of 5 patients who had hyperferritinemia and an iron overload phenotype, but not classic mutations in the HFE gene. Two patients were undergoing phlebotomy and had no iron overload, 1 with metabolic syndrome and no phlebotomy had mild iron overload, and 2 patients had severe iron overload despite phlebotomy. The patients' first-degree relatives also underwent the analysis. We found 5 not previously published mutations: c.-408_-406delCAA in HEE, c.1118G>A (p.G373D), c.1473G>A (p.E491E) and c.2085G>C (p.S695S) in TFR2; and c.-428_-427GG>TT in SLC40A1. Moreover, we found 3 previously published mutations: c.221C>T (p.R71X) in HFE; c.1127C>A (p.A3760) in TFR2; and c.539T>C (p.I180T) in SLC40A1. Four patients were double heterozygous or compound heterozygous for the mutations mentioned above, and the patient with metabolic syndrome was heterozygous for a mutation in the TFR2 gene. Our findings show that hereditary hemochromatosis is clinically and genetically heterogeneous and that acquired factors may modify or determine the phenotype. (C) 2012 Published by Elsevier B.V.