Genotypic and phenotypic spectrum of cytosolic phosphoenolpyruvate carboxykinase deficiency

Pathogenic biallelic variants in PCK1 coding for the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) cause PEPCK-C deficiency, a rare disorder of gluconeogenesis presenting with hypoglycemia, lactic acidosis, and hepatopathy. To date, there has been no systematic analysis of its phenotypic, biochemical, and genetic spectrum.

All currently published individuals and a novel patient with genetically confirmed PEPCK-C deficiency were included. Clinical, biochemical, and genetic findings were analyzed. Protein and in-silico prediction score modeling was applied to analyze potential variant effects.

Thirty-two individuals from 25 families were found, including one previously unreported patient. The typical biochemical pattern was hypoglycemia triggered by catabolic situations, elevated urinary concentrations of tricarboxylic acid cycle metabolites, mildly elevated alanine and aspartate aminotransferase and elevated lactate concentrations in serum. Plasma glutamine concentrations were elevated in some patients and may be a suitable marker for newborn screening. With adequate treatment, biochemical abnormalities usually normalized following a hypoglycemic episode. Symptom onset usually occurred in infancy with a broad range from neonatal age to adulthood. Regardless of the genotype, different phenotypes with a broad clinical spectrum were found. To date, eight genotypes with nine different PCK1 variants were identified, of which alleles with the recurrent variant c.925G > A; p.(Gly309Arg) are predominant and appear to be endemic in the Finnish population. Protein modeling suggests altered manganese- and substrate-binding as superordinate pathomechanisms.

Environmental factors appear to be the main determinant for the phenotype in patients with biallelic variants in PCK1. Based on the biochemical pattern, PEPCK-C deficiency is a recognizable cause of childhood hypoglycemia. It is a treatable disease and early diagnosis is important to prevent metabolic derailment and morbidity. Newborn screening can identify at least a sub-cohort of affected individuals through elevated glutamine concentrations in dry blood.