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Summary

Ammonia, a product of protein catabolism, is detoxified in the liver by the urea cycle in a process that involves mitochondria and cytosol and that is carried out by six enzymes and two mitochondrial amino acid antiporters. Deficiencies in these enzymes and antiporters hamper ammonia detoxification and can cause primary hyperammonemia, a life- and cognition-threatening situation that can occur at any age and that can develop within hours from imbalance between ammonia production and detoxification, as in newborns with urea cycle defects following delivery. Hyperammonemia manifestations are generally unspecific and are mainly neurological, gastrointestinal, or psychiatric. Their hallmark is an unexplained change in consciousness and neurological status; indeed, hyperammonemia should be immediately excluded in any unexplained encephalopathy. Acute hyperammonemia is an emergency requiring urgent establishment of anabolism and avoidance of protein catabolism with rapid initiation (except in citrin deficiency, very rare in the West but not in the Orient) of parenteral glucose infusion and protein restriction. Additional urgent measures include dialysis to remove ammonia, and administration of carbamylglutamate and either l-arginine or l-citrulline, to try to enhance residual urea cycle function, and of the nitrogen scavengers sodium benzoate and/or sodium phenylacetate (or its precursor, phenylbutyrate), to excrete nitrogen without use of the urea cycle. Liver transplantation is curative, correcting hepatic urea cycle function. Prognosis of acute hyperammonemia, still poor, is improving with increasing healthcare professionals’ awareness.

As urea cycle operation needs substrates (ammonia, aspartate, ATP, bicarbonate, ornithine, glutamate, and acetyl coenzyme A), it can be hampered by substrate depletion or by toxic metabolites, as in secondary hyperammonemias. This chapter, in addition to focusing on defects of core urea cycle catalysts, will deal with other genetic conditions that may hamper the supply of ornithine, bicarbonate, glutamate, or ATP and other conditions with an impact on ammonia levels such as glutamine synthetase deficiency and glutamate dehydrogenase superactivity.

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Häberle, J., Rubio, V. (2022). Disorders of Ammonia Detoxification. In: Blau, N., Dionisi Vici, C., Ferreira, C.R., Vianey-Saban, C., van Karnebeek, C.D.M. (eds) Physician's Guide to the Diagnosis, Treatment, and Follow-Up of Inherited Metabolic Diseases. Springer, Cham. https://doi.org/10.1007/978-3-030-67727-5_17

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  • DOI: https://doi.org/10.1007/978-3-030-67727-5_17

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