Fig. 1.

Proposed biochemical pathogenesis of organic acidaemias: propionic acidaemia, methylmalonic acidaemia, isovaleric acidaemia. Genetic defects in enzymes involved in the breakdown of amino acids cause the accumulation of toxic organic acids with disruption of the tricarboxylic acid and urea cycles. Propionic acidaemia is caused by propionyl-CoA carboxylase deficiency, and methylmalonic acidaemia results from methylmalonyl-CoA mutase deficiency [16, 17]. Isovaleric acidaemia is caused by isovaleryl-CoA dehydrogenase deficiency, which is involved in leucine catabolism. Rectangles indicate key affected enzymes: green rectangles indicate the primary affected enzymes (propionyl-CoA carboxylase, methylmalonyl-CoA mutase, isovaleryl-CoA dehydrogenase); blue solid rectangles are positions of primary enzyme blocks. Blue crosses indicate secondary enzyme inhibition; blue texts are enzyme precursors; orange diamonds are key enzyme co-factors. Abbreviations: 2-MCA 2-methylcitrate, CoA coenzyme A, CPS-1 carbamyl phosphate synthetase-1, GLN glutamine, GLU glutamate, H₂O water, IV-CoA isovaleryl-CoA, IVD isovaleryl-CoA dehydrogenase, LEU leucine, MM-CoA methylmalonyl-CoA, MUT methylmalonyl-CoA mutase, NAG N-acetylglutamate, NAGS N-acetylglutamate synthase, NH₃ ammonia, PC pyruvate carboxylase, PCC propionyl-CoA carboxylase, P-CoA propionyl-CoA, PDH pyruvate dehydrogenase complex, TCA tricarboxylic acid, VAL valine. Modified from Kölker et al. 2013 [2], Schiff et al. 2016 [17], and Vianey-Saban et al. 2006 [29]