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

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.