PCK1 – Phosphoenolpyruvate Carboxykinase Deficiency

PCK1 encodes cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), essential for gluconeogenesis and urea cycle anaplerosis. Autosomal recessive biallelic variants were identified in three affected individuals from two unrelated consanguineous families. One patient harbored a homozygous 12-bp deletion in PCK1 (PMID:26971250), and two siblings carried a homozygous missense variant c.134T>C (p.Ile45Thr) (PMID:24863970). All presented with acute liver failure, lactic acidosis and hyperammonemia (HP:0001987), consistent with proximal urea cycle dysfunction.

Enzymatic assays demonstrated virtually absent PEPCK activity in patient cells confirming a loss-of-function mechanism (PMID:26971250). In vitro studies showed that p.Ile45Thr destabilizes PEPCK protein structure and impairs catalytic function (PMID:24863970). These findings support that PCK1 deficiency should be considered in unexplained pediatric acute liver failure with hyperammonemia. Early molecular diagnosis enables prompt dextrose therapy and maintenance of euglycemia to prevent recurrent metabolic crises.

References

• Molecular genetics and metabolism • 2016 • Cytosolic phosphoenolpyruvate carboxykinase deficiency presenting with acute liver failure following gastroenteritis. PMID:26971250
• Molecular genetics and metabolism • 2014 • Three rare diseases in one Sib pair: RAI1, PCK1, GRIN2B mutations associated with Smith-Magenis Syndrome, cytosolic PEPCK deficiency and NMDA receptor glutamate insensitivity. PMID:24863970

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