University of Oulu

Vieira, P, Nagy, II, Rahikkala, E, et al. Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings. J Inherit Metab Dis. 2021; 1- 12. doi:10.1002/jimd.12446

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

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Author: Vieira, Päivi1,2; Nagy, Irina I.3; Rahikkala, Elisa2,4,5;
Organizations: 1Clinic for Children and Adolescents, Oulu University Hospital, Oulu, Finland
2PEDEGO Research Unit and Medical Research Center, Oulu University Hospital and University of Oulu, Oulu, Finland
3Department of Clinical Chemistry, Cancer and Translational Medicine Research Unit, Medical Research Center, University of Oulu and Northern Finland Laboratory Centre NordLab, Oulu University Hospital, Oulu, Finland
4Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland
5Institute of Biomedicine, University of Turku, Turku, Finland
6Department of Pediatrics, Päijät-Häme Central Hospital, Lahti, Finland
7Department of Pediatrics, Lapland Central Hospital, Rovaniemi, Finland
8Department of Clinical Genetics, Turku University Hospital and University of Turku, Turku, Finland
9Department of Pediatrics, North Karelia Central Hospital, Joensuu, Finland
10New Children's Hospital, Helsinki University Hospital, Pediatric Research Center, Helsinki, Finland
Format: article
Version: accepted version
Access: embargoed
Persistent link:
Language: English
Published: John Wiley & Sons, 2021
Publish Date: 2022-10-08


Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) deficiency due to the homozygous PCK1 variant has recently been associated with childhood-onset 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 neonatal hypoglycemia. Hypoglycemic seizures occurred in half of the patients (12 out of 24). The first hypoglycemic episode often occurred at the age of 1–2 years, but it sometimes presented at a later age, and could re-occur during school age or adulthood. This study adds to the laboratory data on PEPCK-C deficiency, confirming the recognizable urine organic acid pattern and identifying deficient ketogenesis as a novel laboratory finding. The phenotype is expanded suggesting that the risk of hypoglycemia may continue into adulthood if predisposing factors are present.

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Series: Journal of inherited metabolic disease
ISSN: 0141-8955
ISSN-E: 1573-2665
ISSN-L: 0141-8955
Volume: In press
DOI: 10.1002/jimd.12446
Type of Publication: A1 Journal article – refereed
Field of Science: 1184 Genetics, developmental biology, physiology
3123 Gynaecology and paediatrics
Funding: Academy of Finland, Grant/Award Number: 338446, 331436; Suomen Lääketieteen Säätiö; The Ester and Uuno Kokki Fund of the Finnish Cultural Heritage; Foundation for Pediatric Research, Finland
Academy of Finland Grant Number: 338446
Detailed Information: 338446 (Academy of Finland Funding decision)
331436 (Academy of Finland Funding decision)
Dataset Reference: The novel variant segregating in family 1 was submitted to the LOVD database ( hosted at Leiden University Medical Center, the Netherlands. Patients' medical records are confidential. Other data supporting the findings are available from the authors upon reasonable request.
Copyright information: © 2021 SSIEM. This is the peer reviewed version of the following article: Vieira, P, Nagy, II, Rahikkala, E, et al. Cytosolic phosphoenolpyruvate carboxykinase deficiency: Expanding the clinical phenotype and novel laboratory findings. J Inherit Metab Dis. 2021; 1- 12, which has been published in final form at This article may be used for non-commercial purposes in accordance with Wiley Terms and Conditions for Self-Archiving.