Cytosolic phosphoenolpyruvate carboxykinase deficiency presenting with acute liver failure following gastroenteritis
Introduction
The availability of whole exome sequencing (WES) has revolutionized the diagnosis of patients with inborn errors of metabolism (IEM), who remain undiagnosed following conventional biochemical and genetic testing [1]. The explosion in reports of novel IEM in recent years is testimony to this [2]. WES can also expand the clinical phenotype of known IEM by the discovery of variants in patients investigated for clinical presentations not previously recognised to be associated with that diagnosis [3]. In these situations, ascribing pathogenicity to such variants may require more detailed functional investigations and in vitro experiments in order to confirm that the detected variants are responsible for the observed presentation. 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. WES performed through the Omics2TreatID study revealed a homozygous 12-bp deletion in PCK1 (MIM 614168) encoding cytosolic phosphoenolpyruvate carboxykinase (PEPCK) as well as a hemizygous variant in PHKA2 (MIM 300798), one of the genes encoding the alpha subunit of glycogen phosphorylase kinase and associated with X-linked glycogen storage disease type IX. Detailed enzymatic studies have subsequently confirmed the pathogenic nature of the PCK1 deletion. PEPCK, an important regulatory step in gluconeogenesis, has only rarely previously been implicated in disease and most historical cases have relied solely upon enzymatic confirmation of the diagnosis. This is difficult due to there being two discrete subcellular isoforms of PEPCK: cytosolic PEPCK (encoded by PCK1) and mitochondrial PEPCK (encoded by PCK2). Total PEPCK activity can also be decreased as a secondary phenomenon. Confirmation of a pathogenic PCK1 variant makes this only the second report in the literature of genetically confirmed cytosolic PEPCK deficiency and suggests this IEM might be an under-recognised cause of transient acute liver failure in childhood.
Section snippets
Ethics
The Omics2TreatID study was approved by the BC Children's & Women's Hospital and University of British Columbia Ethics Board (Vancouver, Canada (H12-00067)). Parents provided informed consent for publication of this report.
NGS sequencing
Genomic DNA was isolated from the peripheral blood of the patient, and unaffected parents using standard techniques. WES was performed for all three family members using the Agilent V4 51Mb with Illumina HiSEQ 2000 100 bp pair-end reads. An in-house designed bioinformatics
Case report
The index case was a nine-month old boy, the fifth child born at term after an uneventful pregnancy and delivery to third-cousin consanguineous parents of Pakistani origin whose elder four children were healthy with normal psychomotor development (Fig. 1).
He presented, after an otherwise uneventful early infancy with normal somatic growth and acquisition of developmental milestones, during an episode of gastroenteritis. After three days of persistent diarrhoea and vomiting, he was taken to
Discussion
Clinical descriptions of enzymatically confirmed PEPCK deficiency were first reported in the 1970s by three groups reporting a total of 4 children: two individual cases and two siblings suffering from hypoglycaemia and lactic acidosis [20], [21], [22]. Where performed, histological evidence of hepatic steatosis was present. Furthermore a case of mitochondrial PEPCK deficiency was reported in a three month old British girl who had fatal liver failure, encephalopathy and hypoglycaemia [23]
Funding
This work was supported by funding from the BC Children's Hospital Foundation (1st Collaborative Area of Innovation, www.tidebc.org), Genome BC (SOF-195 grant), and the Canadian Institutes of Health Research (#301221 grant). Informatics infrastructure was supported by Genome BC and Genome Canada (ABC4DE Project). CvK is a Michael Smith Foundation for Health Research Scholar. CJDR is supported by a CIHR New Investigator award.
Acknowledgments
We gratefully acknowledge the family for their participation in this study; Mr. B. Sayson and Ms. A. Ghani for consenting and coordination of sample collection; Mrs. X. Han for Sanger sequencing; Mrs. M. Higginson for gDNA extraction, sample handling and technical data (University of British Columbia, Vancouver, CA).
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2022, Molecular Genetics and MetabolismCitation Excerpt :Localization and structural consequence of the PCK1 missense variants c.724G > A; p.(Gly242Arg) and c.925G > A; p.(Gly309Arg) in the human PEPCK-C crystal structure (PDB: 1KHF) were visualized using PyMol (v. 2.5.0a; Schrödinger, LLC) installed through Anaconda (v. 2020.11 with Python 3.8.5; Anaconda Inc.). Systematic literature search conducted 31 October 2021 revealed seven peer-reviewed publications on individuals with disease-causing biallelic PCK1 variants, published between 2014 and 31 October 2021, reporting 30 different patients from 23 families with eight different variants [6–8,15–18]. One patient with a previously unknown frameshift variant in compound heterozygous state had been reported in a conference abstract (SSIEM 2016 Annual Symposium) [14].
Underdiagnoses resulting from variant misinterpretation: Time for systematic reanalysis of whole exome data?
2019, European Journal of Medical GeneticsInborn Errors of Metabolism Overview: Pathophysiology, Manifestations, Evaluation, and Management
2018, Pediatric Clinics of North AmericaCitation Excerpt :A recent case of cytosolic phosphoenolpyruvate carboxykinase deficiency in a young child with liver failure, accumulation of tricarboxylic acid cycle metabolites on urine organic acid analysis, and hyperammonaemia with an amino acid profile suggestive of a proximal urea cycle defect, has been described. This is a treatable disease, reversible with intravenous dextrose.27 Investigating individuals with severe hepatic failure is difficult with many pitfalls.