title: Unravelling 5-oxoprolinuria (pyroglutamic aciduria) due to bi-allelic OPLAH mutations: 20 new mutations in 14 families.
abstract: Primary 5-oxoprolinuria (pyroglutamic aciduria) is caused by a genetic defect in the γ-glutamyl cycle, affecting either glutathione synthetase or 5-oxoprolinase. While several dozens of patients with glutathione synthetase deficiency have been reported, with hemolytic anemia representing the clinical key feature, 5-oxoprolinase deficiency due to OPLAH mutations is less frequent and so far has not attracted much attention. This has prompted us to investigate the clinical phenotype as well as the underlying genotype in patients from 14 families of various ethnic backgrounds who underwent diagnostic mutation analysis following the detection of 5-oxoprolinuria. In all patients with 5-oxoprolinuria studied, bi-allelic mutations in OPLAH were indicated. An autosomal recessive mode of inheritance for 5-oxoprolinase deficiency is further supported by the identification of a single mutation in all 9/14 parent sample sets investigated (except for the father of one patient whose result suggests homozygosity), and the absence of 5-oxoprolinuria in all tested heterozygotes. It is remarkable, that all 20 mutations identified were novel and private to the respective families. Clinical features were highly variable and in several sib pairs, did not segregate with 5-oxoprolinuria. Although a pathogenic role of 5-oxoprolinase deficiency remains possible, this is not supported by our findings. Additional patient ascertainment and long-term follow-up is needed to establish the benign nature of this inborn error of metabolism. It is important that all symptomatic patients with persistently elevated levels of 5-oxoproline and no obvious explanation are investigated for the genetic etiology.
authors.affiliation: Bioanalytics & Biochemistry, Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany; Clinical Chemistry & Biochemistry, Children's Research Center, University Children's Hospital, Zürich, Switzerland; Laboratory of Clinical Biochemistry and Metabolism, University Children's Hospital, Freiburg, Germany. Electronic address: joern.oliver.sass@h-brs.de.
authors.forename: Jörn Oliver
authors.initials: JO
authors.lastname: Sass
authors.affiliation: Clinical Chemistry & Biochemistry, Children's Research Center, University Children's Hospital, Zürich, Switzerland.
authors.forename: Corinne
authors.initials: C
authors.lastname: Gemperle-Britschgi
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada; Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada.
authors.forename: Maja
authors.initials: M
authors.lastname: Tarailo-Graovac
authors.affiliation: Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Nisha
authors.initials: N
authors.lastname: Patel
authors.affiliation: Laboratory of Clinical Biochemistry and Metabolism, University Children's Hospital, Freiburg, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Walter
authors.affiliation: Molecular Neurogenomics Group, VIB Department of Molecular Genetics, University of Antwerp, Antwerp, Belgium; Molecular Medicine Center, Department of Medical Chemistry and Biochemistry, Medical University, Sofia, Bulgaria.
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.affiliation: Genetics Division, Department of Pediatrics, King Saud bin Abdulaziz University for Health Sciences King Abdulaziz Medical City, Riyadh, Saudi Arabia.
authors.forename: Majid
authors.initials: M
authors.lastname: Alfadhel
authors.affiliation: Department of Pediatrics, University Hospital Center Zagreb, University of Zagreb, School of Medicine, Zagreb, Croatia.
authors.forename: Ivo
authors.initials: I
authors.lastname: Barić
authors.affiliation: Metabolism Unit, Department of Pediatrics, Ege University Medical Faculty, Izmir, Turkey.
authors.forename: Mahmut
authors.initials: M
authors.lastname: Çoker
authors.affiliation: kbo-Kinderzentrum München, München, Germany.
authors.forename: Aynur
authors.initials: A
authors.lastname: Damli-Huber
authors.affiliation: Children's Hospital, King Fahad Medical City, Riyadh, Saudi Arabia.
authors.forename: Eissa Ali
authors.initials: EA
authors.lastname: Faqeih
authors.affiliation: Center for Molecular Diseases (CMM), Department of Pediatrics, Centre hospitalier universitaire vaudois (CHUV), Lausanne, Switzerland.
authors.forename: Nuria
authors.initials: N
authors.lastname: García Segarra
authors.affiliation: Metabolic Unit, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, ON, Canada.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Geraghty
authors.affiliation: Barneavdelinga, Ålesund sjukehus, Ålesund, Norway.
authors.forename: Bjørn Magne
authors.initials: BM
authors.lastname: Jåtun
authors.affiliation: Metabolism Unit, Department of Pediatrics, Ege University Medical Faculty, Izmir, Turkey.
authors.forename: Sema
authors.initials: S
authors.lastname: Kalkan Uçar
authors.affiliation: Kinder- und Jugendmedizin, Verbundkrankenhaus Bernkastel/Wittlich, Wittlich, Germany.
authors.forename: Merten
authors.initials: M
authors.lastname: Kriewitz
authors.affiliation: Department of Pediatrics, Hospital Ostallgäu-Kaufbeuren, Kaufbeuren, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Rauchenzauner
authors.affiliation: Clinical Institute of Laboratory Diagnostics, University Hospital Center Zagreb, Croatia.
authors.forename: Karmen
authors.initials: K
authors.lastname: Bilić
authors.affiliation: Department of Neurology, Medical University, Sofia, Bulgaria; Department of Cognitive Science and Psychology, New Bulgarian University, Sofia, Bulgaria.
authors.forename: Ivailo
authors.initials: I
authors.lastname: Tournev
authors.affiliation: Bioanalytics & Biochemistry, Department of Natural Sciences, Bonn-Rhein-Sieg University of Applied Sciences, Rheinbach, Germany.
authors.forename: Claudia
authors.initials: C
authors.lastname: Till
authors.affiliation: Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Bryan
authors.initials: B
authors.lastname: Sayson
authors.affiliation: Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Beumer
authors.affiliation: Laboratory of Clinical Biochemistry and Metabolism, University Children's Hospital, Freiburg, Germany.
authors.forename: Cynthia Xin
authors.initials: CX
authors.lastname: Ye
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada; Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada; Child and Family Research Institute, Vancouver, BC, Canada.
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Zhang
authors.affiliation: Child and Family Research Institute, Vancouver, BC, Canada; Department of Pathology, Laboratory Medicine, BC Children's and Women's Hospital, University of British Columbia, Vancouver, Canada.
authors.forename: Hilary
authors.initials: H
authors.lastname: Vallance
authors.affiliation: Developmental Genetics Unit, Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Vancouver, BC, Canada; Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, BC, Canada; Child and Family Research Institute, Vancouver, BC, Canada.
authors.forename: Clara D M
authors.initials: CD
authors.lastname: van Karnebeek
mesh_terms: D000293:Adolescent; D000483:Alleles; D000592:Amino Acid Metabolism, Inborn Errors / Q000201:enzymology / Q000235:genetics* / Q000503:physiopathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005978:Glutathione / Q000378:metabolism; D005981:Glutathione Synthase / Q000172:deficiency* / Q000235:genetics; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D011752:Pyroglutamate Hydrolase / Q000172:deficiency* / Q000235:genetics*; D011761:Pyrrolidonecarboxylic Acid / Q000378:metabolism*
chemical_list: D011752:Pyroglutamate Hydrolase; D005981:Glutathione Synthase; D005978:Glutathione; D011761:Pyrrolidonecarboxylic Acid
keywords: 5-Oxoprolinase; 5-oxoprolinuria; Glutathione synthetase; Pyroglutamic aciduria; γ-glutamyl cycle