Expanding the Genetic Spectrum of Cytosolic Phosphoenolpyruvate Carboxykinase Deficiency
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Background: Cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), encoded byPCK1 gene (MIM # 614168), is a rate-limiting enzyme in gluconeogenesis. It catalyses the decarboxylation of oxaloacetate (OAA) to phosphoenolpyruvate (PEP). Biallelic mutations in PCK1have been reported in patients with hypoglycemia, transient liver dysfunction, and biochemical disturbances suggestive of mitochondrial abnormality and, in some cases, proximal urea cycle defect. Patient: We report a 13-year-old male who presented in infancy with episodes of fasting ketotic hypoglycemia and transient hepatosplenomegaly with mild liver dysfunction. He has, otherwise, normal growth and development. His comprehensive metabolic workup was unremarkable apart from persistent moderate 2-ketoglutaric aciduria with other citric acid cycle metabolites, lactic aciduria and ketonuria. Unlike the previously reported cases, fumaric acid was mildly elevated. Glycogen storage disorders (types 0, Ia, Ib, III, VI, and IXa, b & g) were excluded given the step-wise negative genetic testing. A hypoglycemia gene panel revealed compound heterozygous variants inPCK1gene (NM_002591.3): a previously reported, pathogenic variant (c.925G>A, (p.Gly309Arg)), and a novel, likely pathogenic variant (c.824del, (p.Gly275Valfs*21)). His management was achieved by intravenous dextrose infusion during concurrent illnesses, a bedtime dose of uncooked cornstarch and avoidance of fasting provided via regular meals and snacks. Discussion: The reported phenotypic spectrum of the ultra-rare PEPCK-C deficiency ranges between severe neonatal hypoglycemia, encephalopathy and brain edema leading to death, and a milder phenotype with fasting hypoglycemia and transient liver dysfunction presenting later in life. With our case, we expand the genetic spectrum of the 4 previously reported variants associated with PEPCK-C deficiency.
