Propionic acidemia (PA) is a severe autosomal recessive metabolic disease caused by deficiency of propionyl-CoA carboxylase (PCC). We studied PA transgenic (Pat) mice that lack endogenous PCC but express a hypoactive human PCCA cDNA, permitting their survival. Pat cohorts followed from 3 to 20 weeks of age showed growth failure and lethal crises of lethargy and hyperammonemia, commoner in males (27/50, 54%) than in females (11/52, 21%) and occurring mainly in Pat mice with the most severe growth deficiency. Groups of Pat mice were studied under basal conditions (P-Ba mice) and during acute crises (P-Ac). Plasma acylcarnitines in P-Ba mice, compared to controls, showed markedly elevated C3- and low C2-carnitine, with a further decrease in C2-carnitine in P-Ac mice. These clinical and biochemical findings resemble those of human PA patients. Liver acyl-CoA measurements showed that propionyl-CoA was a minor species in controls (propionyl-CoA/acetyl-CoA ratio, 0.09). In contrast, in P-Ba liver the ratio was 1.4 and in P-Ac liver, 13, with concurrent reductions of the levels of acetyl-CoA and other acyl-CoAs. Plasma ammonia levels in control, P-Ba and P-Ac mice were 109 ± 10, 311 ± 48 and 551 ± 61 μmol/L respectively. Four-week administration to Pat mice, of carglumate (N-carbamyl-L-glutamic acid), an analogue of N-carbamylglutamate, the product of the only acyl-CoA-requiring reaction directly related to the urea cycle, was associated with increased food consumption, improved growth and absence of fatal crises. Pat mice showed many similarities to human PA patients and provide a useful model for studying tissue pathophysiology and treatment outcomes.
Keywords: Coenzyme a; Hyperammonemia; Pathophysiology; Propionic acidemia; Sexual dimorphism.
Copyright © 2021. Published by Elsevier Inc.