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English: Hyperammonaemia in neonates and infants is typically caused by inborn errors of metabolism. Primary urea cycle disorders are caused by congenital deficiency of any of the six urea cycle enzymes: N-acetylglutamate synthase (NAGS), carbamoyl phosphate synthase I (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and arginase 1 (ARG1). These deficiencies result in severe hyperammonaemia and the accumulation of both urea and the substrate of the missing or defective enzyme. For example, the accumulation of carbamoyl phosphate (CP; dashed line) results in greatly increased production and excretion of orotate. Secondary inhibition of the urea cycle is caused by abnormalities that reduce the activity of other enzymes involved in amino acid processing. These deficiencies cause organic acidaemias, such as methylmalonic acidaemia, propionic acidaemia, isovaleric acidaemia and multiple carboxylase deficiency, as well as (typically mild to moderate) hyperammonaemia. Hyperammonaemia can also occur following exposure to drugs, such as valproic acid. Finally, paediatric patients with liver diseases or acute kidney injury are also susceptible to hyperammonaemia owing to impaired metabolism or excretion of urea, respectively68. αKG, α-ketoglutarate; AGC, aspartate–glutamate carrier; GDH, glutamate dehydrogenase; GLNase, glutaminase; GLN-Tx, glutamine transporter; GS, glutamine synthase; NAG, N-acetylglutamate; NOS, nitric oxide synthase; NO, nitric oxide; ORNT1, ornithine translocase.