Hereditary sideroblastic anemia and glucose-6-phosphate dehydrogenase deficiency in a negro family Ananda S. Prasad, … , Charles F. Sing, George J. Brewer J Clin Invest. 1968;47(6):1415-1424. https://doi.org/10.1172/JCI105833. Research Article Detailed clinical and genetic studies have been performed in a Negro family, which segregated for sex-linked sideroblastic anemia and glucose-6-phosphate dehydrogenase (G-6-DP) deficiency. This is the first such pedigree reported. Males affected with sideroblastic anemia had growth retardation, hypochromic microcytic anemia, elevated serum iron, decreased unsaturated iron-binding capacity, increased 59Fe clearance, low 59Fe incorporation into erythrocytes, normal erythrocyte survival (51Cr), normal hemoglobin electrophoretic pattern, erythroblastic hyperplasia of marrow with increased iron, and marked increase in marrow sideroblasts, particularly ringed sideroblasts. Perinuclear deposition of ferric aggregates was demonstrated to be intramitochondrial by electron microscopy. Female carriers of the sideroblastic gene were normal but exhibited a dimorphic population of erythrocytes including normocytic and microcytic cells. The bone marrow studies in the female (mother) showed ringed marrow sideroblasts. Studies of G-6-PD involved the methemoglobin elution test for G-6-PD activity of individual erythrocytes, quantitative G-6- PD assay, and electrophoresis. In the pedigree, linkage information was obtained from a doubly heterozygous woman, four of her sons, and five of her daughters. Three sons were doubly affected, and one was normal. One daughter appeared to be a recombinant. The genes appeared to be linked in the coupling phase in the mother. The maximum likelihood estimate of the recombination value was 0.14. By means of Price-Jones curves, the microcytic red cells in peripheral blood were quantitated in female […] Find the latest version: https://jci.me/105833/pdf Hereditary Sideroblastic Anemia and Glucose- 6-Phosphate Dehydrogenase Deficiency in a Negro Family ANANDA S. PRAsAD, LIBomo TRANCHIDA, EDWARD T. KONNO, LAWRENCE BERMAN, SAMuEL ALBERT, CHARLES F. SING, and GEORGE J. BREwER From the Departments of Medicine and Pathology, Wayne State University, School of Medicine, Detroit, Michigan, Veterans Administration Hospital, Allen Park, Michigan, the Detroit Institute for Cancer Research, and the Depart- ments of Human Genetics and Medicine (Simpson Memorial Institute), University of Michigan Medical School, Ann Arbor, Michigan 48207 A BSTRACT Detailed clinical and genetic stud- Studies of G-6-PD involved the methemoglobin ies have been performed in a Negro family, which elution test for G-6-PD activity of individual segregated for sex-linked sideroblastic anemia and erythrocytes, quantitative G-6-PD assay, and elec- glucose-6-phosphate dehydrogenase (G-6-DP) de- trophoresis. In the pedigree, linkage information ficiency. This is the first such pedigree reported. was obtained from a doubly heterozygous woman, Males affected with sideroblastic anemia had four of her sons, and five of her daughters. Three growth retardation, hypochromic microcytic ane- sons were doubly affected, and one was normal. mia, elevated serum iron, decreased unsaturated One daughter appeared to be a recombinant. The iron-binding capacity, increased 59Fe clearance, genes appeared to be linked in the coupling phase low 59Fe incorporation into erythrocytes, normal in the mother. The maximum likelihood estimate erythrocyte survival (51Cr), normal hemoglobin of the recombination value was 0.14. electrophoretic pattern, erythroblastic hyperplasia By means of Price-Jones curves, the microcytic of marrow with increased iron, and marked in- red cells in peripheral blood were quantitated in crease in marrow sideroblasts, particularly ringed female carriers. The sideroblast count in the bone sideroblasts. Perinuclear deposition of ferric ag- marrow in the mother corresponded closely to the gregates was demonstrated to be intramitochon- percentage of microcytic cells in peripheral blood. drial by electron microscopy. Female carriers of This is the second example in which the cellular the sideroblastic gene were normal but exhibited expression of a sex-linked trait has been docu- a dimorphic population of erythrocytes including mented in the human red cells, the first one being normocytic and microcytic cells. The bone marrow G-6-PD deficiency. The coexistence of the two studies in the female (mother) showed ringed genes in doubly heterozygous females has made it marrow sideroblasts. possible to study correlations in cell counts; our studies showed a strong positive correlation except This paper was presented at the 10th Annual Meeting of the American Society of Hematology, Toronto, Canada, in the probable recombinant in which a reciprocal 3 December 1967. relation held which indicated that X-inactivation Address requests for reprints to Dr. Ananda S. Prasad, was at least regional, rather than locus by locus. Department of Medicine, Wayne State University, School of Medicine, 1400 Chrysler Freeway, Detroit, Mich. INTRODUCTION 48207. Received for publication 27 December 1967 and in re- Several investigators (1-21) have described the vised form 19 February 1968. occurrence of a hypochromic microcytic anemia, The Journal of Clinical Investigation Volume 47 1968 1415 not due to iron deficiency or thalassemia, which plastin time, one stage prothrombin time, accelerator- seemed to be familial. The mode of inheritance globulin, antihemophilic globulin, antithrombin, thrombin appeared to be sex-linked, but sufficient data to time, and euglobulin lysis time (33).1 Studies of G-6-PD involved the methemoglobin elu- determine this with some certainty have been pre- tion test (MET) for G-6-PD activity of individual sented in only a few instances (1-5). In those erythrocytes (34), quantitative G-6-PD assay (35), and cases in which bone marrow studies were per- starch-gel electrophoresis (36). The activities of aldolase, formed, an excessive number of sideroblasts was lactic, and malic dehydrogenases in the red blood cells were determined in several subjects with kits made avail- seen and the entity has been called hereditary sex- able by Calbiochem, Los Angeles, Calif. Pyruvic kinase linked sideroblastic anemia. activity in the red cells was measured according to the This paper presents studies of the first Negro method of Tanaka, Valentine, and Miwa (37). Glycer- family with sex-linked sideroblastic anemia. This aldehyde-3-phosphate dehydrogenase activity of red cells family is also the first to be studied in which glu- was assayed by the method of Bergmeyer (38). cose-6-phosphate dehydrogenase (G-6-PD) de- RESULTS coexists ficiency with sideroblastic anemia. This Pedigree and clinical has provided us with a unique observations in affected opportunity to males study the linkage of the two genes and to study the relationships of the cellular expressions of The pedigree is shown in Fig. 1. The affected 2 the two genes in various genotypes, particularly males (II-2, II-3, and II-16) were 12, 11, and 15 double heterozygotes. yr old, respectively. All three were essentially asymptomatic except for dyspnea on exertion. 5 METHODS yr before this study they were diagnosed elsewhere Three doubly affected boys, seven heterozygous carriers as having anemia of unknown eitology. One male of one or the other gene, three presumed normal, and sibling, II-14, died in 1961, also with a diagnosis three G-6-PD-deficient members of this family were studied in detail. Besides history, physical examination, of anemia of undetermined etiology. This patient, and routine blood tests (fasting blood sugar, blood urea II-14, was said to have a bleeding diathesis. In nitrogen, serum bilirubin, alkaline phosphatase, calcium this connection, it is of interest that one of the phosphorus, and total lipids) complete hematological affected males, II-16, under investigation was ad- studies including bone marrow examination were carried mitted to the hospital during this study because out. The bone marrow smears were stained for iron (22) and the number of abnormal sideroblasts were counted of epistaxis. (23). Normoblasts containing more than five coarse fer- All three boys were anemic and physically ric aggregates or those containing aggregates arranged underdeveloped for their ages (below three per- around the nucleus (ringed type) were considered abnor- centiles of normal curves for height and weight). mal (23). In addition, the bone marrow was fixed in buf- fered glutaraldehyde (24) and postfixed in 1% osmium The spleen was barely palpable in two of the three tetroxide (25) for electron microscopic examination. cases and was not felt in the third. No evidence Fetal hemoglobin and electrophoretic patterns were per- of color blindness was obtained in any of the formed by standard methods (26). Serum iron and un- family members. saturated iron-binding capacity were determined by the Anemia was moderately severe in the affected methods as outlined by Meites and Faulkner (27). The plasma disappearance rate of '9Fe and its incorporation boys (Table I, II-2, II-3, and II-16). Blood films into red cells was also measured (28). Erythrocyte sur- of the peripheral blood stained with Wright's vival was measured by the use of "Cr-labeled red blood stain revealed the presence of markedly hypo- cells (29). Price-Jones curves were obtained by measur- chromic microcytic cells, with extreme poikilo- ing two diameters and taking the average for each red cytosis- Hemoglobin was of the