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Disorders of the Urea Cycle and Related Enzymes

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Inborn Metabolic Diseases

Abstract

Urea cycle disorders (UCDs) are genetic defects causing loss of function of any of the urea cycle (UC) enzymes carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL) and arginase (ARG1); the mitochondrial ornithine/citrulline antiporter (ORC1); and the CPS1-activating enzyme N-acetylglutamate synthase (NAGS). Their combined frequency is about 1:35,000 births, with newborn presentations in at least 25% of cases. NAGS, CPS1 and OTC are mitochondrial and their deficiencies cause hyperammonaemia. The deficiencies of the extramitochondrial enzymes ASS, ASL and ARG1, and of the ORC1 antiporter additionally cause specific alterations in amino acid levels with impact on disease pathogenesis. Deficiencies of carbonic anhydrase Va (CAVA), the liver mitochondrial citrin aspartate/glutamate antiporter and Δ1-pyrroline-5-carboxylate synthetase (P5CS), can cause hyperammonaemia by impairing supply to the UC of bicarbonate, aspartate and de novo made ornithine, respectively. Inheritance of UCDs is autosomal recessive except OTC deficiency, which is X-linked, and P5CS deficiency, which can be dominant or recessive. Acute hyperammonaemia is a clinical emergency occurring in most UCDs and in the transient hyperammonaemia of the newborn (THAN), a rarer condition of unclear etiology. It manifests as irritability, food refusal, vomiting, vegetative instability, hypotonia, convulsions, somnolence, lethargy, coma and death or neurological sequelae if untreated. Therapy of UCDs aims at rapid lowering of ammonia levels by (1) minimizing ammonia production via protein restriction and prevention of catabolism; (2) maximizing ammonia removal using dialytic measures, activation of alternate ammonia scavenging pathways with benzoate and/or phenylacetate or phenylbutyrate, and by enhancing residual UC function with arginine or citrulline where appropriate. Liver transplantation is curative or nearly so for most of these disorders but probably not for ASL deficiency. Importantly, citrin deficiency dramatically differs from other UCDs in that carbohydrates should be limited and high amounts of protein given. NAGS deficiency is virtually cured by giving N-carbamylglutamate to replace the missing N-acetylglutamate. Novel therapies being tested include gene addition and enzyme replacement.

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Authors and Affiliations

  1. Division of Metabolism and Children’s Research Center, University Children’s Hospital, University of Zurich, Zurich, Switzerland

    Johannes Häberle

  2. Structural Enzyme Pathology Laboratory, Instituto de Biomedicina de Valencia, IBV-CSIC & CIBERER-ISCIII, Valencia, Spain

    Vicente Rubio

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  1. Johannes Häberle
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Editors and Affiliations

  1. Paris, France

    Jean-Marie Saudubray

  2. Division of Metabolism, University Children’s Hospital, University of Zurich, Zurich, Switzerland

    Matthias R. Baumgartner

  3. Servicio de Neurologia, Hospital Sant Joan de Deu, Barcelona, Barcelona, Spain

    Ángeles García-Cazorla

  4. Developmental Biology and Medicine, School of Medical Sciences, University of Manchester, Manchester, UK

    John Walter

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Häberle, J., Rubio, V. (2022). Disorders of the Urea Cycle and Related Enzymes. In: Saudubray, JM., Baumgartner, M.R., García-Cazorla, Á., Walter, J. (eds) Inborn Metabolic Diseases. Springer, Berlin, Heidelberg. https://doi.org/10.1007/978-3-662-63123-2_19

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