Myeloperoxidase deficiency and other enzymatic WBC defects causing immunodeficiency
- Sergio D Rosenzweig, MD
Sergio D Rosenzweig, MD
- Department of Laboratory Medicine
- Steven M Holland, MD
Steven M Holland, MD
- Laboratory of Clinical Infectious Diseases
- National Institutes of Health, Bethesda, MD
There are a small number of well-described genetic defects in hematopoietic cell enzymes or transporter proteins that can result in neutrophil dysfunction and immunodeficiency. Two of these, myeloperoxidase (MPO) deficiency and glucose-6-phosphate dehydrogenase (G6PD) deficiency, are relatively common. The others presented in this topic review, glutathione reductase (GR) deficiency, glutathione synthetase (GS) deficiency, and glycogen storage disease type 1b (GSD1b), are rare.
This topic review provides an overview of the genetic defects responsible for each of these disorders as well as their clinical manifestations, diagnosis, and treatment. The focus of this review, however, is the mechanism of neutrophil or leukocyte dysfunction in each condition that leads to immunodeficiency.
Some of these conditions are discussed in other contexts elsewhere. (See "Diagnosis and management of glucose-6-phosphate dehydrogenase deficiency" and "Glucose-6-phosphatase deficiency (glycogen storage disease I, von Gierke disease)" and "Congenital neutropenia".)
Myeloperoxidase (MPO) deficiency (MIM# 254600) is an autosomal recessive inherited disorder with a variable clinical phenotype. It is also the most common primary phagocyte disorder [1-4]:
●1 in 4000 individuals have complete MPO deficiency
Subscribers log in hereLiterature review current through: Jul 2017. | This topic last updated: Oct 26, 2016.References
- Parry MF, Root RK, Metcalf JA, et al. Myeloperoxidase deficiency: prevalence and clinical significance. Ann Intern Med 1981; 95:293.
- Kitahara M, Eyre HJ, Simonian Y, et al. Hereditary myeloperoxidase deficiency. Blood 1981; 57:888.
- Nauseef WM, Root RK, Malech HL. Biochemical and immunologic analysis of hereditary myeloperoxidase deficiency. J Clin Invest 1983; 71:1297.
- Klebanoff SJ, Kettle AJ, Rosen H, et al. Myeloperoxidase: a front-line defender against phagocytosed microorganisms. J Leukoc Biol 2013; 93:185.
- Stiehm ER, Ochs HD, Winkelstein JA. The natural (innate) defense system. In: Immunologic disorders in infants and children, Stiehm ER, Ochs HD, Winkelstein JA (Eds), Elsevier Saunders, Philadelphia 2004. p.258.
- Hampton MB, Kettle AJ, Winterbourn CC. Inside the neutrophil phagosome: oxidants, myeloperoxidase, and bacterial killing. Blood 1998; 92:3007.
- Papayannopoulos V, Metzler KD, Hakkim A, Zychlinsky A. Neutrophil elastase and myeloperoxidase regulate the formation of neutrophil extracellular traps. J Cell Biol 2010; 191:677.
- Rex JH, Bennett JE, Gallin JI, et al. Normal and deficient neutrophils can cooperate to damage Aspergillus fumigatus hyphae. J Infect Dis 1990; 162:523.
- Diamond RD, Clark RA, Haudenschild CC. Damage to Candida albicans hyphae and pseudohyphae by the myeloperoxidase system and oxidative products of neutrophil metabolism in vitro. J Clin Invest 1980; 66:908.
- Weber ML, Abela A, de Repentigny L, et al. Myeloperoxidase deficiency with extensive candidal osteomyelitis of the base of the skull. Pediatrics 1987; 80:876.
- Okuda T, Yasuoka T, Oka N. Myeloperoxidase deficiency as a predisposing factor for deep mucocutaneous candidiasis: a case report. J Oral Maxillofac Surg 1991; 49:183.
- Ludviksson BR, Thorarensen O, Gudnason T, Halldorsson S. Candida albicans meningitis in a child with myeloperoxidase deficiency. Pediatr Infect Dis J 1993; 12:162.
- Nguyen C, Katner HP. Myeloperoxidase deficiency manifesting as pustular candidal dermatitis. Clin Infect Dis 1997; 24:258.
- Chiang AK, Chan GC, Ma SK, et al. Disseminated fungal infection associated with myeloperoxidase deficiency in a premature neonate. Pediatr Infect Dis J 2000; 19:1027.
- Lehrer RI, Cline MJ. Leukocyte myeloperoxidase deficiency and disseminated candidiasis: the role of myeloperoxidase in resistance to Candida infection. J Clin Invest 1969; 48:1478.
- Cech P, Stalder H, Widmann JJ, et al. Leukocyte myeloperoxidase deficiency and diabetes mellitus associated with Candida albicans liver abscess. Am J Med 1979; 66:149.
- Koziol-Montewka M, Magrys A, Paluch-Oles J, et al. MPO and cytokines in the serum of cancer patients in the context of Candida colonization and infection. Immunol Invest 2006; 35:167.
- Magrys A, Koziol-Montewka M, Staroslawska E, et al. Immunological parameters of candidiasis in cancer patients. New Microbiol 2005; 28:355.
- Winterbourn CC, Vissers MC, Kettle AJ. Myeloperoxidase. Curr Opin Hematol 2000; 7:53.
- Brennan ML, Penn MS, Van Lente F, et al. Prognostic value of myeloperoxidase in patients with chest pain. N Engl J Med 2003; 349:1595.
- Hoy A, Leininger-Muller B, Kutter D, et al. Growing significance of myeloperoxidase in non-infectious diseases. Clin Chem Lab Med 2002; 40:2.
- Kutter D, Devaquet P, Vanderstocken G, et al. Consequences of total and subtotal myeloperoxidase deficiency: risk or benefit ? Acta Haematol 2000; 104:10.
- Nauseef WM. How human neutrophils kill and degrade microbes: an integrated view. Immunol Rev 2007; 219:88.
- Larrocha C, Fernández de Castro M, Fontan G, et al. Hereditary myeloperoxidase deficiency: study of 12 cases. Scand J Haematol 1982; 29:389.
- Milligan KL, Mann D, Rump A, et al. Complete Myeloperoxidase Deficiency: Beware the "False-Positive" Dihydrorhodamine Oxidation. J Pediatr 2016; 176:204.
- Lazzato L. Glucose-6-phosphate dehydrogenase deficiency and hemolytic anemia. In: Nathan and Oski's hematology of infancy and childhood, Nathan DG, Orkin SH (Eds), WB Saunders, Philadelphia 1998. p.704.
- Dinauer M. The phagocyte system and disorders of granulopoiesis and granulocyte function.. In: Nathan and Oski's hematology of infancy and childhood, Nathan DG, Orkin SH (Eds), WB Saunders, Philadelphia 1998. p.889.
- 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.
- Mamlok RJ, Mamlok V, Mills GC, et al. Glucose-6-phosphate dehydrogenase deficiency, neutrophil dysfunction and Chromobacterium violaceum sepsis. J Pediatr 1987; 111:852.
- Gray GR, Stamatoyannopoulos G, Naiman SC, et al. Neutrophil dysfunction, chronic granulomatous disease, and non-spherocytic haemolytic anaemia caused by complete deficiency of glucose-6-phosphate dehydrogenase. Lancet 1973; 2:530.
- Ardati KO, Bajakian KM, Tabbara KS. Effect of glucose-6-phosphate dehydrogenase deficiency on neutrophil function. Acta Haematol 1997; 97:211.
- Roos D, van Zwieten R, Wijnen JT, et al. Molecular basis and enzymatic properties of glucose 6-phosphate dehydrogenase volendam, leading to chronic nonspherocytic anemia, granulocyte dysfunction, and increased susceptibility to infections. Blood 1999; 94:2955.
- 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.
- Spolarics Z, Siddiqi M, Siegel JH, et al. Increased incidence of sepsis and altered monocyte functions in severely injured type A- glucose-6-phosphate dehydrogenase-deficient African American trauma patients. Crit Care Med 2001; 29:728.
- Ruwende C, Hill A. Glucose-6-phosphate dehydrogenase deficiency and malaria. J Mol Med (Berl) 1998; 76:581.
- Mason PJ, Bautista JM, Gilsanz F. G6PD deficiency: the genotype-phenotype association. Blood Rev 2007; 21:267.
- Njålsson R, Ristoff E, Carlsson K, et al. Genotype, enzyme activity, glutathione level, and clinical phenotype in patients with glutathione synthetase deficiency. Hum Genet 2005; 116:384.
- Spielberg SP, Boxer LA, Oliver JM, et al. Altered phagocytosis and microtubule function in leukocytes from a patient with severe glutathione synthase deficiency (5-oxoprolinuria). Monogr Hum Genet 1978; 9:90.
- Baehner RL, Boxer LA. Role of membrane vitamin E and cytoplasmic glutathione in the regulation of phagocytic functions of neutrophils and monocytes. Am J Pediatr Hematol Oncol 1979; 1:71.
- Baylor Research Institute, Institute of Metabolic Disease, Dallas; Duke University Medical Center, Pediatric Biochemical Genetics Laboratory. www.baylorhealth.edu/imd (Accessed on May 11, 2007).
- Simon E, Vogel M, Fingerhut R, et al. Diagnosis of glutathione synthetase deficiency in newborn screening. J Inherit Metab Dis 2009; 32 Suppl 1:S269.
- Boxer LA, Oliver JM, Spielberg SP, et al. Protection of granulocytes by vitamin E in glutathione synthetase deficiency. N Engl J Med 1979; 301:901.
- Ristoff E, Mayatepek E, Larsson A. Long-term clinical outcome in patients with glutathione synthetase deficiency. J Pediatr 2001; 139:79.
- Melis D, Fulceri R, Parenti G, et al. Genotype/phenotype correlation in glycogen storage disease type 1b: a multicentre study and review of the literature. Eur J Pediatr 2005; 164:501.
- Janecke AR, Mayatepek E, Utermann G. Molecular genetics of type 1 glycogen storage disease. Mol Genet Metab 2001; 73:117.
- Anderson DC, Mace ML, Brinkley BR, et al. Recurrent infection in glycogenosis type Ib: abnormal neutrophil motility related to impaired redistribution of adhesion sites. J Infect Dis 1981; 143:447.
- Kilpatrick L, Garty BZ, Lundquist KF, et al. Impaired metabolic function and signaling defects in phagocytic cells in glycogen storage disease type 1b. J Clin Invest 1990; 86:196.
- Ambruso DR, McCabe ER, Anderson D, et al. Infectious and bleeding complications in patients with glycogenosis Ib. Am J Dis Child 1985; 139:691.
- Calderwood S, Kilpatrick L, Douglas SD, et al. Recombinant human granulocyte colony-stimulating factor therapy for patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease type 1b. Blood 2001; 97:376.
- McCawley LJ, Korchak HM, Douglas SD, et al. In vitro and in vivo effects of granulocyte colony-stimulating factor on neutrophils in glycogen storage disease type 1B: granulocyte colony-stimulating factor therapy corrects the neutropenia and the defects in respiratory burst activity and Ca2+ mobilization. Pediatr Res 1994; 35:84.
- Donadieu J, Bader-Meunier B, Bertrand Y, et al. Recombinant human G-CSF (Lenograstim) for infectious complications in glycogen storage disease type Ib. Report of 7 cases. Nouv Rev Fr Hematol 1994; 35:529.
- Yamaguchi T, Ihara K, Matsumoto T, et al. Inflammatory bowel disease-like colitis in glycogen storage disease type 1b. Inflamm Bowel Dis 2001; 7:128.
- MYELOPEROXIDASE DEFICIENCY
- Biology of myeloperoxidase
- Clinical manifestations
- - Candida infections
- - Noninfectious diseases
- GLUCOSE-6-PHOSPHATE DEHYDROGENASE DEFICIENCY
- Clinical manifestations
- Evaluation and diagnosis
- GLUTATHIONE PATHWAY ALTERATIONS
- Clinical manifestations
- - Glutathione synthetase deficiency
- - Glutathione reductase deficiency
- GLYCOGEN STORAGE DISEASE 1b
- Clinical manifestations
- Evaluation and diagnosis