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Lookup NU author(s): Dr Mark Anderson
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License (CC BY-NC-ND).
© 2026 The Author(s). American Journal of Medical Genetics Part A published by Wiley Periodicals LLC.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.
Author(s): Bernhardt I, Stabej PLQ, Hart C, De Hora M, Hulley S, Anderson M, Leitch HG, Lemonde H, Ryder B, Davison J
Publication type: Article
Publication status: Published
Journal: American Journal of Medical Genetics, Part A
Year: 2026
Pages: epub ahead of print
Online publication date: 19/01/2026
Acceptance date: 12/01/2026
Date deposited: 02/02/2026
ISSN (print): 1552-4825
ISSN (electronic): 1552-4833
Publisher: John Wiley and Sons Inc
URL: https://doi.org/10.1002/ajmga.70063
DOI: 10.1002/ajmga.70063
Data Access Statement: The data that support the findings of this study are available from the corresponding author upon reasonable request.
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