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

Abstract

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.

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

“…PCKDC (OMIM ) is another new addition to the FDH ( Vieira et al, 2021 ). PCKDC is an inborn error of gluconeogenesis, leading to hypoglycemia in times of fasting or other inadequate carbohydrate intake ( Table 2 ).…”

“…Phosphoenolpyruvate carboxykinase 1 ( PCK1 ) variant c.925G>A, p.Gly309Arg (NM_002591.4) is prevalent in the Finnish population ( Vieira et al, 2021 , 2017 ), with an MAF that is 26 times higher in Finns than in non-Finnish Europeans ( Table 1 , Fig. 2 ) ( Karczewski et al, 2020 ).…”

“…To date, 22 Finnish individuals from 17 families have been identified to carry the homozygous founder variant, about double the number of previously described patients with other PCK1 variants in the world. Additionally, two patients with compound heterozygous PCK1 variants, c.925G>A, p.Gly309Arg and c.716C>T, p.Ser239Leu have been identified in Finland ( Vieira et al, 2021 ). PCKDC cases have been diagnosed throughout Finland without any clear geographical clustering.…”

“…In the Finnish cohort, nearly all the PCKDC patients presented with hypoketotic hypoglycemia, which can be recognized by laboratory screening tests. During hypoglycemic episodes, urine organic acids showed a recognizable abnormal pattern, with low or absent ketonuria, prominent fumaric aciduria, prominent adipic aciduria and, in most cases, prominent lactic aciduria ( Vieira et al, 2017 , 2021 ). Plasma amino acids typically showed low levels of glucogenic amino acids, such as serine and alanine.…”

Hypoglycaemia Metabolic Gene Panel Testing

“…The clinical picture may also mimic Reye syndrome ( 53 , 54 ). Urine organic acids profile shows low or absent ketonuria with presence of fumarate, adipate, succinate, 2-ketoglutarate and glutarate, sometimes ethylmalonate, and in some patients a profile similar to those seen in defects of ketogenesis has been reported ( 55 ). Treatment is based on high carbohydrate diet plus cornstarch, and avoidance of fasting.…”