title: Cytosolic phosphoenolpyruvate carboxykinase deficiency presenting with acute liver failure following gastroenteritis.
abstract: We report a patient from a consanguineous family who presented with transient acute liver failure and biochemical patterns suggestive of disturbed urea cycle and mitochondrial function, for whom conventional genetic and metabolic investigations for acute liver failure failed to yield a diagnosis. Whole exome sequencing revealed a homozygous 12-bp deletion in PCK1 (MIM 614168) encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK); enzymatic studies subsequently confirmed its pathogenic nature. We propose that PEPCK deficiency should be considered in the young child with unexplained liver failure, especially where there are marked, accumulations of TCA cycle metabolites on urine organic acid analysis and/or an amino acid profile with hyperammonaemia suggestive of a proximal urea cycle defect during the acute episode. If suspected, intravenous administration of dextrose should be initiated. Long-term management comprising avoidance of fasting with the provision of a glucose polymer emergency regimen for illness management may be sufficient to prevent future episodes of liver failure. This case report provides further insights into the (patho-)physiology of energy metabolism, confirming the power of genomic analysis of unexplained biochemical phenotypes.
authors.affiliation: Birmingham Children's Hospital, Birmingham, UK. Electronic address: saikat.santra@bch.nhs.uk.
authors.forename: Saikat
authors.initials: S
authors.lastname: Santra
authors.affiliation: Genetics and Genome Biology Program, Peter Gilgan Centre for Research and Learning, Toronto, Canada.
authors.forename: Jessie M
authors.initials: JM
authors.lastname: Cameron
authors.affiliation: Centre for Molecular Medicine, Child & Family Research Institute, Vancouver, Canada.
authors.forename: Casper
authors.initials: C
authors.lastname: Shyr
authors.affiliation: Centre for Molecular Medicine, Child & Family Research Institute, Vancouver, Canada; Department of Pediatrics, University of British Columbia, Canada.
authors.forename: Linhua
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
authors.forename: Britt
authors.initials: B
authors.lastname: Drögemöller
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, Canada; Centre for Molecular Medicine, Child & Family Research Institute, Vancouver, Canada; Department of Pediatrics, University of British Columbia, Canada.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Ross
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, Canada; Centre for Molecular Medicine, Child & Family Research Institute, Vancouver, Canada.
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
authors.affiliation: Department of Laboratory Medicine - Translational Metabolic Laboratory, Radboudumc, Nijmegen, The Netherlands.
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.affiliation: Nijmegen Center for Mitochondrial Disorders, Department of Pediatrics, Translational Metabolic Laboratory, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.affiliation: Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Girish
authors.initials: G
authors.lastname: Gupte
authors.affiliation: Birmingham Children's Hospital, Birmingham, UK.
authors.forename: Mary Anne
authors.initials: MA
authors.lastname: Preece
authors.affiliation: Centre for Molecular Medicine, Child & Family Research Institute, Vancouver, Canada; Department of Pediatrics, University of British Columbia, Canada. Electronic address: cvankarnebeek@cw.bc.ca.
authors.forename: Clara D
authors.initials: CD
authors.lastname: van Karnebeek
mesh_terms: D001483:Base Sequence; D002239:Carbohydrate Metabolism, Inborn Errors / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D003241:Consanguinity; D059472:Exome; D005759:Gastroenteritis / Q000209:etiology* / Q000235:genetics; D005947:Glucose / Q000008:administration & dosage / Q000627:therapeutic use; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008107:Liver Diseases / Q000175:diagnosis* / Q000188:drug therapy / Q000235:genetics; D017114:Liver Failure, Acute / Q000209:etiology* / Q000235:genetics; D008297:Male; D010375:Pedigree; D010729:Phosphoenolpyruvate Carboxykinase (GTP) / Q000172:deficiency* / Q000235:genetics; D017384:Sequence Deletion
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; C521898:PCK1 protein, human; D010729:Phosphoenolpyruvate Carboxykinase (GTP); D005947:Glucose
keywords: Hepatopathy; Hyperammonaemia; Lactic acidosis; PCK1; PEPCK; Treatment