Novel missense variants in PCK1 gene cause cytosolic PEPCK deficiency with growth failure from inadequate caloric intake

Oishi, Kimihiko; Siegel, Casey M; Cork, Emalyn; Chen, Hongjie; Imagawa, Eri

doi:10.1038/s10038-020-00823-8

Cited by 6 publications

(3 citation statements)

References 16 publications

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“…Our patient had high levels of ammonia during some episodes of hypoglycemia. Cases of high ammonia levels with PEPCK-C deficiency were also described by Santra et al [ 13 ] and Oishi et al [ 14 ]. In addition to the role of PEPCK-C in gluconeogenesis and glyceroneogenesis, it is also the major cataplerotic enzyme that helps remove citric acid cycle anions left after the entry of the carbon skeletons of amino acids in the Krebs cycle.…”

Section: Discussionmentioning

confidence: 72%

Pathogenic Potential of a PCK1 Gene Variant in Cytosolic PEPCK Deficiency: A Compelling Case Study

Duś-Żuchowska,

Nowak,

Kałużny

et al. 2024

Am J Case Rep

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Patient: Female, 1-year-old Final Diagnosis: PEPCK deficiency Symptoms: Hypoglycaemia Clinical Procedure: — Specialty: Metabolic Disorders and Diabetics • Pediatrics and Neonatology Objective: Rare disease Background: Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency is an extremely rare autosomal recessive inherited error of metabolism in which gluconeogenesis is impaired, resulting in life-threatening episodes of hypoglycemia and metabolic acidosis. The diagnosis of gluconeogenesis disorders is challenging. In the diagnostic pathway, the molecular test plays a paramount role. Case Report: The aim of the paper is to present the case report of a girl with recurrent episodes of severe hypoglycemia, in whom molecular diagnosis enabled the confirmation of PEPCK – C deficiency. The patient experienced 4 episodes of severe hypoglycemia. Most of them were accompanied by hyperlacticaemia, metabolic acidosis, and elevated liver enzymes. All of the metabolic decompensations were triggered by infectious agents. The episodes resolved after continuous infusion of high-dose glucose. Due to the recurrent character of the disease, a genetic condition was suspected. The differential diagnosis included metabolic and endocrinological causes of hypoglycemia. Two variants in the PCK1 gene were detected: c.265G>A p.(Glu89Lys) in exon 3 and c.925G>A p.(Gly309Arg) in exon 6. As c.925G>A p.(Gly309Arg) is a known pathogenic variant, the second variant was first described in June 2023 in the ClinVar database and described as “with unknown clinical significance”. Conclusions: According to the clinical symptoms observed in the presented case, the variant c.265G>A p.(Glu89Lys) in PCK1 gene should be considered likely pathogenic. We suggest considering molecular diagnostics in every patient presented with recurrent, severe hypoglycemia with accompanying liver damage as most accurate, feasible, and reliable method.

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Section: Discussionmentioning

confidence: 72%

Pathogenic Potential of a PCK1 Gene Variant in Cytosolic PEPCK Deficiency: A Compelling Case Study

Duś-Żuchowska,

Nowak,

Kałużny

et al. 2024

Am J Case Rep

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“…Liver transaminases and urine organic acids may take weeks or months to normalize. A recent report described a Hispanic PCKDC patient without documented hypoglycemia but presenting with growth failure ( Oishi et al, 2021 ).…”

Section: The Fdhmentioning

confidence: 99%

The Finnish genetic heritage in 2022 – from diagnosis to translational research

Uusimaa

Kettunen

Varilo

et al. 2022

Disease Models &Amp; Mechanisms

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Isolated populations have been valuable for the discovery of rare monogenic diseases and their causative genetic variants. Finnish disease heritage (FDH) is an example of a group of hereditary monogenic disorders caused by single major, usually autosomal-recessive, variants enriched in the population due to several past genetic drift events. Interestingly, distinct subpopulations have remained in Finland and have maintained their unique genetic repertoire. Thus, FDH diseases have persisted, facilitating vigorous research on the underlying molecular mechanisms and development of treatment options. This Review summarizes the current status of FDH, including the most recently discovered FDH disorders, and introduces a set of other recently identified diseases that share common features with the traditional FDH diseases. The Review also discusses a new era for population-based studies, which combine various forms of big data to identify novel genotype–phenotype associations behind more complex conditions, as exemplified here by the FinnGen project. In addition to the pathogenic variants with an unequivocal causative role in the disease phenotype, several risk alleles that correlate with certain phenotypic features have been identified among the Finns, further emphasizing the broad value of studying genetically isolated populations.

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“…Cytosolic PEPCK deficiency is a rare inborn error of metabolism, with less than 10 genetically confirmed cases described in the literature 1,11‐15 . Additionally, there are some earlier reports based on biochemical data only 16‐19 .…”

Section: Introductionmentioning

confidence: 99%

Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings

Vieira

Nagy

Rahikkala

et al. 2021

J of Inher Metab Disea

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Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency due to the homozygous PCK1 variant has recently been associated with childhoodonset hypoglycemia with a recognizable pattern of abnormal urine organic acids. In this study, 21 children and 3 adult patients with genetically confirmed PEPCK-C deficiency were diagnosed during the years 2016 to 2019 and the available biochemical and clinical data were collected. All patients were ethnic Finns. Most patients (22 out of 24) had a previously published homozygous PCK1 variant c.925G>A. Two patients had a novel compound heterozygous PCK1 variant c.925G>A and c.716C>T. The laboratory results showed abnormal urine organic acid profile with increased tricarboxylic acid cycle intermediates and inadequate ketone body production during hypoglycemia. The hypoglycemic episodes manifested predominantly in the morning. Infections, fasting or poor food intake, heavy exercise, alcohol consumption, and breastfeeding were identified as triggering factors. Five patients presented with Päivi Vieira and Irina I. Nagy contributed equally as first authors to this study.Johanna Uusimaa and Päivi Myllynen contributed equally as senior authors.

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Novel missense variants in PCK1 gene cause cytosolic PEPCK deficiency with growth failure from inadequate caloric intake

Cited by 6 publications

References 16 publications

Pathogenic Potential of a PCK1 Gene Variant in Cytosolic PEPCK Deficiency: A Compelling Case Study

Pathogenic Potential of a PCK1 Gene Variant in Cytosolic PEPCK Deficiency: A Compelling Case Study

The Finnish genetic heritage in 2022 – from diagnosis to translational research

Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings

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