Hyperammonaemia can either be due to increased production or decreased detoxification of ammonia, and there are many underlying causes for both of these groups.
Hyperammonaemia is life-threatening because of potential neuro-toxicity. Untreated, it can cause death, and, even when treated, patients may suffer significant neurological consequences.
Hyperammonaemia can be either primary (i.e. a defect within the urea cycle) or secondary (i.e. a defect outside the urea cycle leading to a decrease in normal urea cycle function).
Causes of increased ammonia production:
Causes of decreased ammonia detoxification:
Causes of secondary hyperammonaemia:
Fig 5 below illustrates the mechanisms by which various metabolites influence urea cycle function.
Legend: Figure showing sites of action of various compounds on urea cycle function by either leading to inhibition of enzymes (NAGS or CPS1) or to a decrease in intermediate substrates (both forms of inhibition are depicted as (-).
HIHA: Hyperinsulinism-hyperammonaemia syndrome; FAOD: Fatty acid oxidation defects; PDHCD: Pyruvate dehydrogenase complex disorders; OA: Organic acidemias; HHH: Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome; PC: Pyruvate carboxylase defect; Citrin: Citrullinaemia type 2; LPI: Lysinuric protein intolerance; P5CS: Pyrroline-5-carboxylate synthetase defect. The site of action of valproate has also been added. (+) Depicts the stimulatory effect of NAG on CPS1.
See Ref. 3 and 4 for further information.
You will learn more about hyperammonaemic disorders at a later stage of this course.