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OrphanAnesthesia
I. Okonkwo · G. Stuart · N.F. Ekasumara · T.K. Huncke

Urea cycle disorders

Schlüsselwörter Urea Cycle Disorders; ICD 10: E72.2; Disorders of urea cycle metabolism, UCDs, Hyperammonaemia; N-acetylglutamate synthase deficiency; ICD 10: E72.2; NAGS deficiency, NAGSD; Carbamylphosphate synthetase deficiency; ICD 10: E72.2; CPS deficiency, CPS 1 deficiency, Carbamoyl phosphate synthetase 1 deficiency, CPS1D; Ornithine transcarbamylase deficiency; ICD 10: E72.4; OTC deficiency, OTCD; Ornithine transcarbamylase deficiency; ICD 10: E72.2; Argininosuccinate synthetase deficiency, ASSD; Argininosuccinate lyase deficiency; ICD 10: E72.2; Argininosuccinic aciduria, ASL deficiency, ASLD; Argininaemia; ICD 10: E72.2; Arginase deficiency, Hyperargininemia, ARG1D
Keywords Urea Cycle Disorders; ICD 10: E72.2; Disorders of urea cycle metabolism, UCDs, Hyperammonaemia; N-acetylglutamate synthase deficiency; ICD 10: E72.2; NAGS deficiency, NAGSD; Carbamylphosphate synthetase deficiency; ICD 10: E72.2; CPS deficiency, CPS 1 deficiency, Carbamoyl phosphate synthetase 1 deficiency, CPS1D; Ornithine transcarbamylase deficiency; ICD 10: E72.4; OTC deficiency, OTCD; Ornithine transcarbamylase deficiency; ICD 10: E72.2; Argininosuccinate synthetase deficiency, ASSD; Argininosuccinate lyase deficiency; ICD 10: E72.2; Argininosuccinic aciduria, ASL deficiency, ASLD; Argininaemia; ICD 10: E72.2; Arginase deficiency, Hyperargininemia, ARG1D
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Summary

The urea cycle is a series of reactions that occur in the liver whereby ammonia, the neurotoxic by-product of amino acid deamination, is converted to urea. Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification and arginine synthesis caused by deficiencies in any one of the six enzymes or two transporters of the urea cycle pathway – see Figure 1 [1,2,43].

There are 6 UCDs in total. Ornithine transcarbamylase deficiency (OTCD), the most common, is inherited as X-linked dominant. The remaining four are of autosomal recessive inheritance and include carbamoylphosphate synthetase-1 deficiency (CPS1D), argininosuccinate synthetase deficiency (ASSD/citrullinaemia type 1), argininosuccinate lyase deficiency (ASLD), arginase-1 deficiency and N-acetylglutamate synthase deficiency (NAGSD).
The peri-operative period is important for patients with UCDs because physiological and psychological stress can induce a catabolic state resulting in acute metabolic decompen¬sation and a potentially fatal hyperammonaemia characterised by cerebral oedema and encephalopathy [2–4,43]. UCDs are the commonest inborn errors of hepatic metabolism with an incidence of 1:8,000 to 1:44,000 live births [2–5,44]. Disease prevalence is thought to exceed current estimation due to the absence of reliable new-born screening and under-diagnosis of fatal cases. Multiple mutations have been recognised and some disorders such as OTCD have heterogeneous penetrance and phenotypes, due to variability in gene activation and hepatocyte expression [1,2,8–15,43].
Protein is not stored within the body but exists in balance between anabolism and catabolism. Excess protein (from dietary intake or catabolic processes) is deaminated and these amino acids are then broken down to release nitrogen as ammonia. Excess ammonia has toxic effects particularly within the central nervous system. The urea cycle takes place primarily within the liver and converts ammonia into urea which is renally excreted. See Figure 1:  
 
Partial or complete absence of these mitochondrial enzymes impairs the conversion of orni-thine and carbamoylphosphate to urea and results in the accumulation of ammonia and, depending on the disorder in question, also citrulline (argininosuccinate synthetase deficien¬cy), argininosuccinic acid (argininosuccinate lyase deficiency), fumaric acid (arginase-1 defi-ciency), glutamine (carbamoyl phosphate synthetase 1 deficiency) or arginine (ornithine transcarbamylase deficiency) [6].
OTCD is the commonest of the five urea cycle defects (approximately 60 % of UCD patients) followed by ASLD (approximately 16 %) and ASSD/citrullinaemia type 1 (approximately 14 %) [6–8].
Severe neonatal forms of the disease (in OTCD: typically, hemizygous males) present in the first few days of life as “floppy infants” with hyperammonaemia, a respiratory alkalosis, hyper-ventilation, vomiting, irritability and lethargy which can progress to seizures, encephalopathy, coma and death [1–2,4–5,10,43]. Milder forms of the disease (in OTCD: more commonly, heterozygous females) present anytime from infancy to adulthood and can be triggered by illness, stress or other events associated with protein catabolism [1–2,8–15,43].
Complications of UCDs include developmental delay, intellectual disability and progressive liver damage. People with later onset UCDs may experience episodes of altered mental state (e.g. delirium, erratic behaviour, reduced consciousness), headaches, vomiting, ataxia, aver-sion to protein foods, anorexia, abnormal GI function and seizures [1–2,7,43].
Liver transplantation is curative [2, 9–10,14,16–19,43]. Existing neurological damage cannot be corrected, making early treatment and avoidance of decompensation vital. Peri-operative management aims to avoid metabolic decompensation by minimising physical and psycho-logical stress; maintaining optimal hydration status; preventing protein catabolism; and facilitating nitrogen excretion [1–4,10,18,43].

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