Cytosolic phosphoenolpyruvate carboxykinase deficiency presenting with acute liver failure following gastroenteritis

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Highlights

  • PEPCK deficiency should be considered in the young child with unexplained liver failure.

  • Metabolite accumulation suggesting acute TCA cycle and/or proximal urea cycle dysfunction may indicate PEPCK deficiency

  • If suspected, intravenous administration of dextrose should be initiated and metabolic abnormalities may rapidly improve.

  • Fasting avoidance and the use of a glucose polymer emergency regimen may prevent future episodes of liver failure.

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.

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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