Fig. 2: Clinical manifestations of hyperammonaemia.

The clinical features of an acute hyperammonaemic episode are influenced by the age of the patient and the underlying cause of hyperammonaemia — that is, the specific urea cycle enzyme deficiency or organic acidaemia. a | In neonates, early symptoms include lethargy, loss of appetite and vomiting. If ammonia levels continue to rise, symptoms progress to hypotonia and hyperventilation resulting in respiratory alkalosis. Severe hyperammonaemia is characterized by an acute encephalopathy, seizures, and, if untreated, coma and death. b | Late-onset hyperammonaemia (that is, in infants, children and adults) typically results from a partial or mild urea cycle enzyme deficiency exacerbated by exposure to stressors such as drug treatment. These individuals typically present with failure to thrive and abdominal symptoms, accompanied by psychiatric manifestations such as irritability, learning disabilities, delusion and psychosis. Patients might additionally have neurological symptoms, including neurodevelopmental delay, seizures and hemiplegia. The psychiatric and neurological manifestations of hyperammonaemia are attributable to increased brain levels of ammonia, which is metabolized to glutamine by astrocytes. The resulting high extracellular levels of potassium and glutamine cause increased intracellular osmolality and cerebral oedema, leading to neuronal damage and the release of inflammatory cytokines.