title: Severe glucose-6-phosphate dehydrogenase deficiency leads to susceptibility to infection and absent NETosis.
abstract: Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common enzymatic disorder of red blood cells in human subjects, causing hemolytic anemia linked to impaired nicotinamide adenine dinucleotide phosphate (NADPH) production and imbalanced redox homeostasis in erythrocytes. Because G6PD is expressed by a variety of hematologic and nonhematologic cells, a broader clinical phenotype could be postulated in G6PD-deficient patients. We describe 3 brothers with severe G6PD deficiency and susceptibility to bacterial infection.
  
  
  
  We sought to study the molecular pathophysiology leading to susceptibility to infection in 3 siblings with severe G6PD deficiency.
  
  
  
  Blood samples of 3 patients with severe G6PD deficiency were analyzed for G6PD enzyme activity, cellular oxidized nicotinamide adenine dinucleotide phosphate/NADPH levels, phagocytic reactive oxygen species production, neutrophil extracellular trap (NET) formation, and neutrophil elastase translocation.
  
  
  
  In these 3 brothers strongly reduced NADPH oxidase function was found in granulocytes, leading to impaired NET formation. Defective NET formation has thus far been only observed in patients with the NADPH oxidase deficiency chronic granulomatous disease, who require antibiotic and antimycotic prophylaxis to prevent life-threatening bacterial and fungal infections.
  
  
  
  Because severe G6PD deficiency can be a phenocopy of chronic granulomatous disease with regard to the cellular and clinical phenotype, careful evaluation of neutrophil function seems mandatory in these patients to decide on appropriate anti-infective preventive measures. Determining the level of G6PD enzyme activity should be followed by analysis of reactive oxygen species production and NET formation to decide on required antibiotic and antimycotic prophylaxis.
authors.affiliation: Division of Immunology, University Children's Hospital and Children's Research Centre, Zurich, Switzerland.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Siler
authors.affiliation: Division of Immunology, University Children's Hospital and Children's Research Centre, Zurich, Switzerland.
authors.forename: Susana
authors.initials: S
authors.lastname: Romao
authors.affiliation: Division of Immunology, University Children's Hospital and Children's Research Centre, Zurich, Switzerland.
authors.forename: Emilio
authors.initials: E
authors.lastname: Tejera
authors.affiliation: Division of Immunology, University Children's Hospital and Children's Research Centre, Zurich, Switzerland.
authors.forename: Oleksandr
authors.initials: O
authors.lastname: Pastukhov
authors.affiliation: Division of Immunology, University Children's Hospital and Children's Research Centre, Zurich, Switzerland.
authors.forename: Elena
authors.initials: E
authors.lastname: Kuzmenko
authors.affiliation: Division of Immunology, University Children's Hospital and Children's Research Centre, Zurich, Switzerland.
authors.forename: Rocio G
authors.initials: RG
authors.lastname: Valencia
authors.affiliation: Division of Immunology, University Children's Hospital and Children's Research Centre, Zurich, Switzerland.
authors.forename: Virginia
authors.initials: V
authors.lastname: Meda Spaccamela
authors.affiliation: Division of Infectious Diseases and Immunology, Dr. von Haunersches Kinderspital, University Childrens Hospital, Ludwig-Maximilians-University, Munich, Germany.
authors.forename: Bernd H
authors.initials: BH
authors.lastname: Belohradsky
authors.affiliation: Division of Hematology, University Children's Hospital and Children's Research Centre, Zurich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Speer
authors.affiliation: Division of Hematology, University Children's Hospital and Children's Research Centre, Zurich, Switzerland.
authors.forename: Markus
authors.initials: M
authors.lastname: Schmugge
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Centre Ulm, Ulm, Germany.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Kohne
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Centre Ulm, Ulm, Germany.
authors.forename: Manfred
authors.initials: M
authors.lastname: Hoenig
authors.affiliation: Children's Hospital Ostalbklinikum, Aalen, Germany.
authors.forename: Joachim
authors.initials: J
authors.lastname: Freihorst
authors.affiliation: Department of Pediatrics and Adolescent Medicine, University Medical Centre Ulm, Ulm, Germany.
authors.forename: Ansgar S
authors.initials: AS
authors.lastname: Schulz
authors.affiliation: Division of Immunology, University Children's Hospital and Children's Research Centre, Zurich, Switzerland; Zurich Centre for Integrative Human Physiology, University of Zurich, Zurich, Switzerland; Centre for Applied Biotechnology and Molecular Medicine, University of Zurich, Zurich, Switzerland; Swiss Center for Regenerative Medicine, University of Zurich, University of Zurich, Zurich, Switzerland. Electronic address: janine.reichenbach@kispi.uzh.ch.
authors.forename: Janine
authors.initials: J
authors.lastname: Reichenbach
mesh_terms: D001424:Bacterial Infections; D002648:Child; D004198:Disease Susceptibility; D004912:Erythrocytes / Q000378:metabolism; D065206:Extracellular Traps / Q000378:metabolism*; D005954:Glucosephosphate Dehydrogenase / Q000235:genetics / Q000378:metabolism; D005955:Glucosephosphate Dehydrogenase Deficiency / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism; D006098:Granulocytes / Q000378:metabolism; D006801:Humans; D007223:Infant; D019272:Leukocyte Elastase / Q000378:metabolism; D008297:Male; D009249:NADP / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D017382:Reactive Oxygen Species; D009249:NADP; D005954:Glucosephosphate Dehydrogenase; D019272:Leukocyte Elastase
keywords: Glucose-6-phosphate dehydrogenase deficiency; NADPH; chronic granulomatous disease; immunodeficiency; innate immunity; neutrophil extracellular trap formation