Cytosolic Phosphoenoylpyruvate Carboxykinase Deficiency: Clinical, Biochemical, and Genetic Features of Five...

Cytosolic phosphoenoylpyruvate carboxykinase (PEPCK-C) is an essential, rate-limiting enzyme in the gluconeogenesis pathway. PEPCK-C deficiency presents with hypoglycaemia, hyperlactataemia and hepatopathy, and was first reported in association with bi-allelic PCK1 variants in 2014. A Finnish cohort with a common homozygous variant (c.925G>A, p.(Gly309Arg)) is well-described, but few other genotypes are reported. Five non-Finnish probands with PEPCK-C deficiency with novel genotypes are presented. All five presented with hypoglycaemia (hypoketotic in three), lactic acidosis, and elevated transaminases. Age at presentation was newborn to 3 years. Two presented with hypoglycaemic seizures after overnight fasting during intercurrent infection. Prominent renal manifestations were noted in two, including proximal tubulopathy with bicarbonate wasting, and acute renal failure, respectively, with markedly elevated plasma glutamine in both. Urine organic acid analysis identified elevated lactate, dicarboxylic aciduria, and tricarboxylic acid cycle metabolites, especially fumarate which was detected in 3/5. PCK1 genotypes included homozygous missense variants c.1211C>T, p.(Ser404Leu) and c.265G>A, p.(Glu89Lys), or compound heterozygous variants including c.824del, p.(Gly275Valfs21); c.496G>A, p.(Val166Met); c.961 + 2 T>C; c.204del, p.(Leu69), and c.728A>G p.(Lys243Arg). A severe phenotype with failure to thrive, short fasting tolerance, liver dysfunction, and tubulopathy was noted in one individual harboring compound heterozygous splicing and nonsense variants. Evidence from in silico analyses and the specific phenotype supported the pathogenicity of novel missense variants. These patients reinforce the recognizable presentation of PEPCK-C deficiency while highlighting renal manifestations and expanding the genotypic spectrum.