A Novel PCK1 Gene Variant Associated With Cytosolic Phosphoenolpyruvate Carboxykinase Deficiency: Two Siblings With Different Clinical Presentations

TL;DR

A new PCK1 gene variant is linked to a rare metabolic disorder causing liver failure and high glutamine levels, with early treatment helping to reverse symptoms.

Contribution

A novel PCK1 frameshift variant, c.1833_1834del, is identified and classified as likely pathogenic in PEPCK-C deficiency.

Findings

PEPCK-C deficiency can present as reversible acute liver failure with hyperglutaminemia.

Early glucose infusion can reverse acute liver failure in PEPCK-C deficiency.

Molecular testing is recommended for unexplained acute liver failure with elevated glutamine.

Abstract

Cytosolic phosphoenolpyruvate carboxykinase (PEPCK‐C) deficiency is a rare autosomal recessive gluconeogenesis disorder caused by variants in the PCK1 gene. Clinically, PEPCK‐C deficiency is characterized by recurrent episodes of fasting‐induced hypoglycemia, liver dysfunction, and seizures, with the first hypoglycemic episode typically occurring in the neonatal period or in early childhood. We report a case of PEPCK‐C deficiency in an 8‐year‐old who presented with transient severe acute liver and kidney failure, accompanied by markedly elevated glutamine levels as the initial manifestation of the disease. The acute liver failure was reversible following continuous glucose infusion. Next‐generation sequencing identified two variants in the PCK1 gene: one previously known pathogenic variant, c.925G>A p.(Gly309Arg), and a second previously unreported variant, c.1833_1834del p.(Glu611AspfsTer16). These variants were confirmed to be in a compound heterozygous state. Based on the patient's clinical presentation, the second variant was classified as likely pathogenic. Subsequent genetic testing of family members revealed that the patient's 12‐year‐old sister has the same PCK1 variants but remains asymptomatic to date. Given the clinical findings, we propose that the c.1833_1834del p.(Glu611AspfsTer16) variant in the PCK1 gene should be classified as likely pathogenic. We recommend considering molecular diagnostics for PEPCK‐C deficiency in patients presenting with severe acute liver failure and elevated glutamine levels, as early diagnosis and intervention may lead to a reversible outcome.

PEPCK‐C deficiency may present as reversible severe acute liver failure with hyperglutaminemia.A novel PCK1 frameshift variant, c.1833_1834del, was identified and classified as likely pathogenic.Early glucose infusion can reverse acute liver failure in PEPCK‐C deficiency.Molecular testing should be considered in unexplained acute liver failure with elevated glutamine.

PEPCK‐C deficiency may present as reversible severe acute liver failure with hyperglutaminemia.

A novel PCK1 frameshift variant, c.1833_1834del, was identified and classified as likely pathogenic.

Early glucose infusion can reverse acute liver failure in PEPCK‐C deficiency.

Molecular testing should be considered in unexplained acute liver failure with elevated glutamine.