Genetics and pathophysiology of glucose-6-phosphate dehydrogenase deficiency
- Bertil Glader, MD, PhD
Bertil Glader, MD, PhD
- Professor of Pediatrics
- Stanford University School of Medicine
- Section Editors
- Stanley L Schrier, MD
Stanley L Schrier, MD
- Editor-in-Chief — Hematology
- Section Editor — Myeloproliferative Disorders; Red Blood Cell Disorders
- Professor of Medicine
- Stanford University School of Medicine
- Benjamin A Raby, MD, MPH
Benjamin A Raby, MD, MPH
- Section Editor — Genetics
- Associate Professor of Medicine
- Harvard Medical School
Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked disorder, is the most common enzymatic disorder of red blood cells in humans, affecting more than 400 million people worldwide [1-4]. The clinical expression of G6PD variants encompasses a spectrum of hemolytic syndromes. Affected patients are most often asymptomatic, but many patients have episodic anemia, while a few have chronic hemolysis.
With the most prevalent G6PD variants (G6PD A- and G6PD Mediterranean), hemolysis is induced in children and adults by the sudden destruction of older, more deficient erythrocytes after exposure to drugs having a high redox potential (including the antimalarial drug primaquine and certain sulfa drugs) or to fava beans, selected infections, or metabolic abnormalities (table 1). However, in the neonate with G6PD deficiency, decreased bilirubin elimination may play an important role in the development of jaundice (see 'Jaundice in neonates' below) [5,6].
Normal enzyme function and the genetics and pathophysiology of G6PD deficiency, including its possible role in protecting against severe malaria, will be reviewed here. The clinical manifestations, diagnosis, and treatment of this disorder are discussed separately. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase deficiency".)
A historical review of the discovery of this defect, its clinical manifestations, detection, population genetics, and molecular biology, written by Dr. Ernest Beutler, a pioneer in the understanding of this disorder, is available .
FUNCTION OF G6PD
Glucose-6-phosphate dehydrogenase catalyzes the initial step in the hexose monophosphate (HMP or pentose phosphate) shunt, oxidizing glucose-6-phosphate to 6-phosphogluconolactone and reducing nicotinamide adenine dinucleotide phosphate (NADP) to NADPH (figure 1). The HMP shunt is the only red cell source of NADPH, a cofactor important in glutathione metabolism.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Ruwende C, Khoo SC, Snow RW, et al. Natural selection of hemi- and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria. Nature 1995; 376:246.
- Cappellini MD, Fiorelli G. Glucose-6-phosphate dehydrogenase deficiency. Lancet 2008; 371:64.
- Glader B. Hereditary hemolytic anemias due to red blood cell enzyme disorders. In: Wintrobe's Clinical Hematology, 13th edition, Greer JP, Arber D, Glader B, et al (Eds), Wolters Kluwer/Lippincott, Williams & Wilkins, Philadelphia 2014. p.728.
- Mason PJ, Bautista JM, Gilsanz F. G6PD deficiency: the genotype-phenotype association. Blood Rev 2007; 21:267.
- Kaplan M, Hammerman C. Severe neonatal hyperbilirubinemia. A potential complication of glucose-6-phosphate dehydrogenase deficiency. Clin Perinatol 1998; 25:575.
- Kaplan M, Hammerman C. Glucose-6-phosphate dehydrogenase deficiency: a hidden risk for kernicterus. Semin Perinatol 2004; 28:356.
- Beutler E. Glucose-6-phosphate dehydrogenase deficiency: a historical perspective. Blood 2008; 111:16.
- KIRKMAN HN, HENDRICKSON EM. Sex-linked electrophoretic difference in glucose-6-phosphate dehydrogenase. Am J Hum Genet 1963; 15:241.
- Martini G, Toniolo D, Vulliamy T, et al. Structural analysis of the X-linked gene encoding human glucose 6-phosphate dehydrogenase. EMBO J 1986; 5:1849.
- Persico MG, Viglietto G, Martini G, et al. Isolation of human glucose-6-phosphate dehydrogenase (G6PD) cDNA clones: primary structure of the protein and unusual 5' non-coding region. Nucleic Acids Res 1986; 14:2511.
- Takizawa T, Huang IY, Ikuta T, Yoshida A. Human glucose-6-phosphate dehydrogenase: primary structure and cDNA cloning. Proc Natl Acad Sci U S A 1986; 83:4157.
- BEUTLER E, YEH M, FAIRBANKS VF. The normal human female as a mosaic of X-chromosome activity: studies using the gene for C-6-PD-deficiency as a marker. Proc Natl Acad Sci U S A 1962; 48:9.
- Hsia YE, Miyakawa F, Baltazar J, et al. Frequency of glucose-6-phosphate dehydrogenase (G6PD) mutations in Chinese, Filipinos, and Laotians from Hawaii. Hum Genet 1993; 92:470.
- Au WY, Lam V, Pang A, et al. Glucose-6-phosphate dehydrogenase deficiency in female octogenarians, nanogenarians, and centenarians. J Gerontol A Biol Sci Med Sci 2006; 61:1086.
- Beutler E. G6PD deficiency. Blood 1994; 84:3613.
- Mason PJ. New insights into G6PD deficiency. Br J Haematol 1996; 94:585.
- Hirono A, Kuhl W, Gelbart T, et al. Identification of the binding domain for NADP+ of human glucose-6-phosphate dehydrogenase by sequence analysis of mutants. Proc Natl Acad Sci U S A 1989; 86:10015.
- Miwa S, Fujii H. Molecular basis of erythroenzymopathies associated with hereditary hemolytic anemia: tabulation of mutant enzymes. Am J Hematol 1996; 51:122.
- Beutler E. The genetics of glucose-6-phosphate dehydrogenase deficiency. Semin Hematol 1990; 27:137.
- Nomenclature of glucose-6-phosphate dehydrogenase in man. Am J Hum Genet 1967; 19:757.
- WHO Scientific Group. Standardization of procedures for the study of glucose-6-phosphate dehydrogenase. WHO Tech Rep Ser 366, Geneva 1967.
- Beutler E. The molecular biology of enzymes of erythrocyte metabolism. In: The Molecular Basis of Blood Disease, Stamatoyannopoulos G, Nienhus AW, Majerus PW, et al. (Eds), WB Saunders, Philadelphia 1993.
- BOYER SH, PORTER IH, WEILBACHER RG. Electrophoretic heterogeneity of glucose-6-phosphate dehydrogenase and its relationship to enzyme deficiency in man. Proc Natl Acad Sci U S A 1962; 48:1868.
- Yoshida A. A single amino Acid substitution (asparagine to aspartic Acid) between normal (b+) and the common negro variant (a+) of human glucose-6-phosphate dehydrogenase. Proc Natl Acad Sci U S A 1967; 57:835.
- Reys L, Manso C, Stamatoyannopoulos G. Genetic studies on southeastern Bantu of Mozambique. I. Variants of glucose-6-phosphate dehydrogenase. Am J Hum Genet 1970; 22:203.
- Piomelli S, Corash LM, Davenport DD, et al. In vivo lability of glucose-6-phosphate dehydrogenase in GdA- and GdMediterranean deficiency. J Clin Invest 1968; 47:940.
- Morelli A, Benatti U, Gaetani GF, De Flora A. Biochemical mechanisms of glucose-6-phosphate dehydrogenase deficiency. Proc Natl Acad Sci U S A 1978; 75:1979.
- Hirono A, Beutler E. Molecular cloning and nucleotide sequence of cDNA for human glucose-6-phosphate dehydrogenase variant A(-). Proc Natl Acad Sci U S A 1988; 85:3951.
- Beutler E, Kuhl W, Vives-Corrons JL, Prchal JT. Molecular heterogeneity of glucose-6-phosphate dehydrogenase A-. Blood 1989; 74:2550.
- Beutler E. Glucose-6-phosphate dehydrogenase: new perspectives. Blood 1989; 73:1397.
- Vulliamy TJ, D'Urso M, Battistuzzi G, et al. Diverse point mutations in the human glucose-6-phosphate dehydrogenase gene cause enzyme deficiency and mild or severe hemolytic anemia. Proc Natl Acad Sci U S A 1988; 85:5171.
- Oppenheim A, Jury CL, Rund D, et al. G6PD Mediterranean accounts for the high prevalence of G6PD deficiency in Kurdish Jews. Hum Genet 1993; 91:293.
- McCurdy PR, Kirkman HN, Naiman JL, et al. A Chinese variant of glucose-6-phosphate dehydrogenase. J Lab Clin Med 1966; 67:374.
- Glader BE. Glucose-6-phosphate dehydrogenase deficiency and related disorders of hexose monophosphate shunt and glutathione metabolism. In: Wintrobe's Clinical Hematology, 10th ed, Lee GR, Foerster J, Lukens J, et al. (Eds), Williams & Wilkins, Baltimore 1176.
- Cappellini MD, Martinez di Montemuros F, De Bellis G, et al. Multiple G6PD mutations are associated with a clinical and biochemical phenotype similar to that of G6PD Mediterranean. Blood 1996; 87:3953.
- ALVING AS, CARSON PE, FLANAGAN CL, ICKES CE. Enzymatic deficiency in primaquine-sensitive erythrocytes. Science 1956; 124:484.
- Yoshida A, Stamatoyannopoulos G, Motulsky AG. Negro variant of glucose-6-phosphate dehydrogenase deficiency (A-) in man. Science 1967; 155:97.
- Corash L, Spielberg S, Bartsocas C, et al. Reduced chronic hemolysis during high-dose vitamin E administration in Mediterranean-type glucose-6-phosphate dehydrogenase deficiency. N Engl J Med 1980; 303:416.
- Arese P, De Flora A. Pathophysiology of hemolysis in glucose-6-phosphate dehydrogenase deficiency. Semin Hematol 1990; 27:1.
- Jacob HS. Mechanisms of Heinz body formation and attachment to red cell membrane. Semin Hematol 1970; 7:341.
- Allen DW, Flynn TP, Johnson GJ. Erythrocyte membrane protein changes in glucose-6-phosphate dehydrogenase mutants with chronic hemolytic disease: an example of postsynthetic modification of membrane proteins. Prog Clin Biol Res 1982; 97:33.
- Coetzer T, Zail S. Membrane protein complexes in GSH-depleted red cells. Blood 1980; 56:159.
- Rifkind RA. Heinz body anemia: an ultrastructural study. II. Red cell sequestration and destruction. Blood 1965; 26:433.
- Tizianello A, Pannacciulli I, Ajmar F, Salvidio E. Sites of destruction of red cells in G-6-PD deficient Caucasians and in phenylhydrazine treated patients. Scand J Haematol 1968; 5:116.
- DOXIADIS SA, VALAES T. THE CLINICAL PICTURE OF GLUCOSE 6-PHOSPHATE DEHYDROGENASE DEFICIENCY IN EARLY INFANCY. Arch Dis Child 1964; 39:545.
- Meloni T, Costa S, Cutillo S. Haptoglobin, hemopexin, hemoglobin and hematocrit in newborns with erythrocyte glucose-6-phosphate dehydrogenase deficiency. Acta Haematol 1975; 54:284.
- Valaes T. Severe neonatal jaundice associated with glucose-6-phosphate dehydrogenase deficiency: pathogenesis and global epidemiology. Acta Paediatr Suppl 1994; 394:58.
- Kaplan M, Renbaum P, Levy-Lahad E, et al. Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia. Proc Natl Acad Sci U S A 1997; 94:12128.
- RAMOT B, FISHER S, SZEINBERG A, et al. A study of subjects with erythrocyte glucose-6-phosphate dehydrogenase deficiency. II. Investigation of leukocyte enzymes. J Clin Invest 1959; 38:2234.
- Miller DR, Wollman MR. A new variant of glucose-6-phosphate dehydrogenase deficiency hereditary hemolytic anemia, G6PD Cornell: erythrocyte, leukocyte, and platelet studies. Blood 1974; 44:323.
- Schilirò G, Russo A, Mauro L, et al. Leukocyte function and characterization of leukocyte glucose-6-phosphate dehydrogenase in Sicilian mutants. Pediatr Res 1976; 10:739.
- Vives Corrons JL, Feliu E, Pujades MA, et al. Severe-glucose-6-phosphate dehydrogenase (G6PD) deficiency associated with chronic hemolytic anemia, granulocyte dysfunction, and increased susceptibility to infections: description of a new molecular variant (G6PD Barcelona). Blood 1982; 59:428.
- van Bruggen R, Bautista JM, Petropoulou T, et al. Deletion of leucine 61 in glucose-6-phosphate dehydrogenase leads to chronic nonspherocytic anemia, granulocyte dysfunction, and increased susceptibility to infections. Blood 2002; 100:1026.
- Luzzatto L. Genetics of red cells and susceptibility to malaria. Blood 1979; 54:961.
- Nagel RL, Roth EF Jr. Malaria and red cell genetic defects. Blood 1989; 74:1213.
- Tishkoff SA, Varkonyi R, Cahinhinan N, et al. Haplotype diversity and linkage disequilibrium at human G6PD: recent origin of alleles that confer malarial resistance. Science 2001; 293:455.
- Ruwende C, Hill A. Glucose-6-phosphate dehydrogenase deficiency and malaria. J Mol Med (Berl) 1998; 76:581.
- Siniscalco, M, et al. Favism and thalassemia in Sardinia and their relationship to malaria. Nature 1961; 190:1179.
- Luzzatto L, Usanga FA, Reddy S. Glucose-6-phosphate dehydrogenase deficient red cells: resistance to infection by malarial parasites. Science 1969; 164:839.
- Luzzatto L, Sodeinde O, Martini G. Genetic variation in the host and adaptive phenomena in Plasmodium falciparum infection. Ciba Found Symp 1983; 94:159.
- Roth EF Jr, Raventos-Suarez C, Rinaldi A, Nagel RL. Glucose-6-phosphate dehydrogenase deficiency inhibits in vitro growth of Plasmodium falciparum. Proc Natl Acad Sci U S A 1983; 80:298.
- Cappadoro M, Giribaldi G, O'Brien E, et al. Early phagocytosis of glucose-6-phosphate dehydrogenase (G6PD)-deficient erythrocytes parasitized by Plasmodium falciparum may explain malaria protection in G6PD deficiency. Blood 1998; 92:2527.
- Roth EF Jr, Schulman S, Vanderberg J, Olson J. Pathways for the reduction of oxidized glutathione in the Plasmodium falciparum-infected erythrocyte: can parasite enzymes replace host red cell glucose-6-phosphate dehydrogenase? Blood 1986; 67:827.
- Usanga EA, Luzzatto L. Adaptation of Plasmodium falciparum to glucose 6-phosphate dehydrogenase-deficient host red cells by production of parasite-encoded enzyme. Nature 1985; 313:793.
- Yoshida A, Roth EF Jr. Glucose-6-phosphate dehydrogenase of malaria parasite Plasmodium falciparum. Blood 1987; 69:1528.
- Giribaldi G, Ulliers D, Mannu F, et al. Growth of Plasmodium falciparum induces stage-dependent haemichrome formation, oxidative aggregation of band 3, membrane deposition of complement and antibodies, and phagocytosis of parasitized erythrocytes. Br J Haematol 2001; 113:492.
- Griffiths MJ, Ndungu F, Baird KL, et al. Oxidative stress and erythrocyte damage in Kenyan children with severe Plasmodium falciparum malaria. Br J Haematol 2001; 113:486.
- Roth EF Jr, Ruprecht RM, Schulman S, et al. Ribose metabolism and nucleic acid synthesis in normal and glucose-6-phosphate dehydrogenase-deficient human erythrocytes infected with Plasmodium falciparum. J Clin Invest 1986; 77:1129.
- FUNCTION OF G6PD
- GENETICS OF G6PD
- G6PD and its variants
- Classification of G6PD variants
- - Wild-type enzyme
- - G6PD A- variant
- - G6PD Mediterranean variant
- PATHOPHYSIOLOGY OF G6PD DEFICIENCY
- Hemolytic anemia
- Jaundice in neonates
- G6PD in other hematopoietic cells
- Possible protection against malaria
- INFORMATION FOR PATIENTS