title: Novel homozygous PCK1 mutation causing cytosolic phosphoenolpyruvate carboxykinase deficiency presenting as childhood hypoglycemia, an abnormal pattern of urine metabolites and liver dysfunction.
abstract: Clinical and laboratory data were collected from three Finnish patients including a sibling pair and another unrelated child with unexplained childhood hypoglycemia. Transient elevation of alanine transaminase, lactate and tricarboxylic acid cycle intermediates, especially fumarate, were noticed in urine organic acid analysis. Exome sequencing was performed for the patients and their parents. A novel homozygous PCK1 c.925G>A (p.G309R) mutation was detected in all affected individuals. COS-1 cells transfected with mutant PCK1 transcripts were used to study the pathogenic nature of the detected variant. The COS-1 transfected cells showed the mutant gene to be incapable of producing a normally functioning cytosolic phosphoenolpyruvate carboxykinase (PEPCK) enzyme. This report further delineates the clinical phenotype of isolated cytosolic PEPCK deficiency and offers a metabolic pattern helping to recognize these patients. Cytosolic PEPCK deficiency should be considered in the differential diagnosis of children presenting with hypoglycemia, hepatic dysfunction and elevated tricarboxylic acid intermediates in urinary organic acid analysis.
authors.affiliation: PEDEGO Research Unit, University of Oulu, Clinic for Children and Adolescents, Oulu University Hospital, Oulu, Finland. Electronic address: paivi.vieira@fimnet.fi.
authors.forename: Päivi
authors.initials: P
authors.lastname: Vieira
authors.affiliation: Genetics and Genome Biology, Peter Gilgan Center for Research and Learning, 686 Bay Street, Toronto, Ontario M5G0A4, Canada.
authors.forename: Jessie
authors.initials: J
authors.lastname: Cameron
authors.affiliation: PEDEGO Research Unit, Clinical Genetics, University of Oulu, Medical Research Center Oulu, Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
authors.forename: Elisa
authors.initials: E
authors.lastname: Rahikkala
authors.affiliation: PEDEGO Research Unit, Clinical Genetics, University of Oulu, Medical Research Center Oulu, Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
authors.forename: Riikka
authors.initials: R
authors.lastname: Keski-Filppula
authors.affiliation: Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada.
authors.forename: Lin-Hua
authors.initials: LH
authors.lastname: Zhang
authors.affiliation: Department of Clinical Inherited Metabolic Disorders, Birmingham Children's Hospital, Steelhouse Lane, Birmingham B4 6NH, United Kingdom.
authors.forename: Saikat
authors.initials: S
authors.lastname: Santra
authors.affiliation: Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada.
authors.forename: Allison
authors.initials: A
authors.lastname: Matthews
authors.affiliation: Northern Finland Laboratory Centre Nordlab, Oulu University Hospital, Oulu, Finland.
authors.forename: Päivi
authors.initials: P
authors.lastname: Myllynen
authors.affiliation: PEDEGO Research Unit, University of Oulu, Clinic for Children and Adolescents, Oulu University Hospital, Oulu, Finland.
authors.forename: Matti
authors.initials: M
authors.lastname: Nuutinen
authors.affiliation: PEDEGO Research Unit, Clinical Genetics, University of Oulu, Medical Research Center Oulu, Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland.
authors.forename: Jukka S
authors.initials: JS
authors.lastname: Moilanen
authors.affiliation: Radboud Center for Mitochondrial Medicine, Department of Pediatrics, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Centogene AG, The Rare Disease Company, Rostock, Germany; Albrecht Kossel Institute for Neuroregeneration, University of Rostock, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Rolfs
authors.affiliation: PEDEGO Research Unit, University of Oulu, Clinic for Children and Adolescents, Oulu University Hospital, Oulu, Finland; Medical Research Center Oulu and Biocenter Oulu, University of Oulu, Finland.
authors.forename: Johanna
authors.initials: J
authors.lastname: Uusimaa
authors.affiliation: Department of Pediatrics, Centre for Molecular Medicine and Therapeutics, BC Children's Hospital Research Institute, University of British Columbia, Vancouver, Canada; Department of Pediatrics, Emma Children's Hospital, Academic Medical Centre, Amsterdam, The Netherlands.
authors.forename: Clara D M
authors.initials: CDM
authors.lastname: van Karnebeek
mesh_terms: D000818:Animals; D019556:COS Cells; D002239:Carbohydrate Metabolism, Inborn Errors / Q000175:diagnosis* / Q000503:physiopathology; D002648:Child; D002522:Chlorocebus aethiops; D059472:Exome; D005260:Female; D020022:Genetic Predisposition to Disease; D006720:Homozygote; D006801:Humans; D007003:Hypoglycemia / Q000209:etiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008099:Liver / Q000503:physiopathology*; D008107:Liver Diseases / Q000175:diagnosis* / Q000503:physiopathology; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000172:deficiency* / Q000235:genetics; D017422:Sequence Analysis, DNA / Q000379:methods; D014556:Urine / Q000737:chemistry*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C521898:PCK1 protein, human; D010729:Phosphoenolpyruvate Carboxykinase (GTP)
keywords: Autosomal recessive; Child; Impaired gluconeogenesis; Recurrent hypoglycemia