Hyperammonaemia as a cause of psychosis in an adolescent

European Journal of Pediatrics;2003, Vol. 162 Issue 11, p773

November 2003

Diseases that cause hyperammonaemia usually appear during the neonatal period or during the first months of life as severe neurological metabolic distress. In some cases, as the one reported here, the age of onset and initial symptoms are non-specific and the episodes of acute metabolic encephalopathy may be attributed to encephalitis, poisoning or psychiatric problems. Our patient had N-acetyl glutamate synthetase deficiency due to a lack of activation by L-arginine. Treatment with N-carbamylglutamate was successful in maintaining normal ammonia levels. Conclusion: we emphasise the importance of measuring ammonia levels in patients with neurological or psychiatric symptoms as part of their diagnostic work-up.

Biochem Pharmacol. 2010 Nov 1;80(9):1303-8. Epub  2010 Jul 21.

Glutamine as a mediator of ammonia neurotoxicity: A critical appraisal.

Source

Department of Neurotoxicology, Mossakowski Medical Research Centre, Polish Academy of Sciences, Warsaw, Poland. jalb@cmdik.pan.pl

Abstract

Ammonia is a major neurotoxin implicated in hepatic encephalopathy (HE). Here we discuss evidence that many aspects of ammonia toxicity in HE-affected brain are mediated by glutamine (Gln), synthesized in excess from ammonia and glutamate by glutamine synthetase (GS), an astrocytic enzyme. The degree to which Gln is increased in brains of patients with HE was found to positively correlate with the grade of HE. In animals with HE, a GS inhibitor, methionine sulfoximine (MSO), reversed a spectrum of manifestations of ammonia toxicity, including brain edema and increased intracranial pressure, even though MSO itself increased brain ammonia levels. MSO inhibited, while incubation with Gln reproduced the oxidative stress and cell swelling observed in ammonia-exposed cultured astrocytes. Recent studies have shown that astrocytes swell subsequent to Gln transport into mitochondria and its degradation back to ammonia, which then generates reactive oxygen species and the mitochondrial permeability transition. This sequence of events led to the formulation of the “Trojan Horse” hypothesis. Further verification of the role of Gln in the pathogenesis of HE will have to account for: (1) modification of the effects of Gln by interaction of astrocytes with other CNS cells; and (2) direct effects of Gln on these cells. Recent studies have demonstrated a “Trojan Horse”-like effect of Gln in microglia, as well as an interference by Gln with the activation of the NMDA/NO/cGMP pathway by ammonia as measured in whole brain, a process that likely also involves neurons.

Copyright © 2010 Elsevier Inc. All rights reserved.

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