Cytosolic PEPCK deficiency caused by a novel homozygous frame-shift variant presenting as resolved hypoglycemia and acute liver failure at birth

Abstract

Cytosolic phosphoenolpyruvate carboxykinase (PEPCK) is an enzyme encoded by the PCK1 gene and plays a rate limiting step in gluconeogenesis occurring mainly in the liver during prolonged fasting. Biallelic deficiency of this enzyme results in a rare inborn error of metabolism disorder (OMIM # 261680). The main clinical and laboratory manifestations include fasting hypoglycemia and lactic acidosis with urinary excretion of Tricarboxylic Acid (TCA) cycles metabolites, particularly fumarate. The initial presentation varies between individuals in terms of age at initial presentation and clinical manifestations, however clinical information is lacking as it was diagnosed so far in less than 30 patients with a total of 6 different mutations which are all either missense or splice variants. We describe the first homozygous frame-shift mutation in the PCK1 gene, leading to cytosolic PEPCK deficiency. This resulted in transient hypoglycemia and acute liver failure with extreme hyperferritinemia (>40,000 ng/ml) during the first days of life. This severe very early-onset presentation that was not described earlier expands our clinical and genetic spectrum of this rare metabolic disorder.