PCK1 – Cytosolic phosphoenolpyruvate carboxykinase deficiency

Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency is an autosomal recessive disorder caused by biallelic variants in the PCK1 gene, encoding a rate-limiting enzyme of gluconeogenesis. Affected individuals present with fasting-induced hypoglycemia, lactic acidosis, and hepatopathy, often triggered by infections, exercise, or poor intake.

In a cohort of 24 Finnish patients with genetically confirmed PEPCK-C deficiency (22 homozygous c.925G>A; p.Gly309Arg, 2 compound heterozygous c.925G>A and c.716C>T; p.Ser239Leu), hypoglycemic episodes were predominant in the morning with five cases of neonatal hypoglycemia and twelve cases of hypoglycemic seizures ([PMID:34622459]). A subsequent analysis incorporating all published individuals plus one novel patient identified 32 affected individuals from 25 families, confirming the recurrent c.925G>A (p.Gly309Arg) allele as an endemic founder variant in Finns ([PMID:35868242]).

Inheritance is autosomal recessive; segregation in multiple sibships supports biallelic transmission. The variant spectrum includes missense alleles (nine reported to date) with recurrent p.Gly309Arg, novel p.Ser239Leu, and a likely pathogenic p.Glu89Lys identified in a case report of severe hypoglycemia and metabolic acidosis ([PMID:38656928]).

Biochemical studies demonstrate a characteristic urine organic acid profile with elevated tricarboxylic acid cycle intermediates and deficient ketone body production during hypoglycemia ([PMID:34622459]). The case report of p.Glu89Lys further linked this variant to recurrent hypoglycemia, metabolic acidosis, and elevated transaminases, underscoring the value of molecular testing in diagnostic pathways ([PMID:38656928]).

Protein modeling suggests that pathogenic PCK1 variants, particularly p.Gly309Arg, disrupt manganese and substrate binding, consistent with a loss-of-function mechanism ([PMID:35868242]). Functional assays in patient samples confirm impaired enzymatic activity, though animal models have not yet been described.

Overall, cumulative genetic and experimental evidence supports a Strong autosomal recessive association between PCK1 and cytosolic PEPCK deficiency. Early molecular diagnosis enables tailored metabolic management to prevent life-threatening hypoglycemic crises. PEPCK-C deficiency should be considered in any individual with fasting-induced hypoglycemia and a distinctive organic acid signature. Key take-home: biallelic PCK1 variants define a treatable gluconeogenesis disorder with persistent hypoglycemia risk into adulthood.

References

• Journal of inherited metabolic disease • 2022 • Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings. PMID:34622459
• Molecular genetics and metabolism • 2022 • Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency. PMID:35868242
• The American journal of case reports • 2024 • Pathogenic Potential of a PCK1 Gene Variant in Cytosolic PEPCK Deficiency: A Compelling Case Study. PMID:38656928

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