Pyruvate carboxylase deficiency: An underestimated cause of lactic acidosis

Abstract

Pyruvate carboxylase (PC) is a biotin-containing mitochondrial enzyme that catalyzes the conversion of pyruvate to oxaloacetate, thereby being involved in gluconeogenesis and in energy production through replenishment of the tricarboxylic acid (TCA) cycle with oxaloacetate. PC deficiency is a very rare metabolic disorder. We report on a new patient affected by the moderate form (the American type A). Diagnosis was nearly fortuitous, resulting from the revision of an initial diagnosis of mitochondrial complex IV (C IV) defect. The patient presented with severe lactic acidosis and pronounced ketonuria, associated with lethargy at age 23 months. Intellectual disability was noted at this time. Amino acids in plasma and organic acids in urine did not show patterns of interest for the diagnostic work-up. In skin fibroblasts PC showed no detectable activity whereas biotinidase activity was normal. We had previously reported another patient with the severe form of PC deficiency and we show that she also had secondary C IV deficiency in fibroblasts. Different anaplerotic treatments in vivo and in vitro were tested using fibroblasts of both patients with 2 different types of PC deficiency, type A (patient 1) and type B (patient 2). Neither clinical nor biological effects in vivo and in vitro were observed using citrate, aspartate, oxoglutarate and bezafibrate. In conclusion, this case report suggests that the moderate form of PC deficiency may be underdiagnosed and illustrates the challenges raised by energetic disorders in terms of diagnostic work-up and therapeutical strategy even in a moderate form.

Deep Learning/Artificial Intelligence and Blood-Based DNA Epigenomic Prediction of Cerebral Palsy

“…We also identified a hypomethylated pyruvate carboxylase gene ( PC ) in our study. PC is an active component of tricarboxylic acid (TCA) cycle that produces lactic acid [39]. Lactic acidosis has been linked to CP [40].…”

Hungry for your alanine: when liver depends on muscle proteolysis

“…After 60 hours of fasting, V PC clearly increased during the subsequent alanine infusion, suggesting that replenishing citric acid (Krebs) cycle intermediates could have accelerated V CS. Humans with inborn V PC deficiency show severe depletion of anaplerotic flux (18), and liver-specific knockdown of pyruvate carboxylase decreases mitochondrial oxidation. Also, thyroid hormones can markedly affect hepatic oxidation, and the observation of lower serum thyroid-stimulating hormone and unchanged total thyroid hormone levels does not completely preclude any effect of the active free hormone or its metabolites (19).…”

Case report of Takotsubo syndrome following seizures in a patient with pyruvate carboxylase deficiency

“…Pyruvate carboxylase is a mitochondrial enzyme that is involved in gluconeogenesis and energy production. This enzyme catalyzes the conversion of pyruvate to oxaloacetate when abundant acetyl CoA is available ( Figure 5 ), 9 and the excess pyruvate is converted to lactate. When there is a deficiency in pyruvate carboxylase, this leads to an excess of pyruvate, which is broken down to lactate within cells.…”