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Treatment of urea cycle disorders includes a low‐protein diet, adequate calorie intake, alternative‐pathway treatment for hyperammonaemic crises, and dialysis if needed. Alternative‐pathway treatment consists of giving phenylacetate and benzoate so that waste nitrogen is excreted as phenylacetylglutamine and N‐benzoylglycine rather than producing ammonia. It was first suggested by Brusilow and colleagues in 1979 and now a multicentre US study extending over 25 years has been reported by researchers including Dr Brusilow (Gregory M Enns and colleagues. New England Journal of Medicine 2007;356:2282–92; see also editorial, ibid: 2321–2).
The open‐label, uncontrolled study, primarily at specialised metabolic diseases centres, included 299 patients with five different enzyme deficiencies: ornithine transcarbamylase deficiency (164 patients; 86 male, 78 female), argininosuccinate synthetase deficiency (80), carbamyl phosphate synthetase deficiency (41), argininosuccinate lyase deficiency (11) and arginase deficiency (3). They were treated during crises with intravenous sodium phenylacetate and sodium benzoate with added arginine hydrochloride in doses appropriate to the specific diagnosis.
In all, 250 (84%) of the children survived. There were 1181 episodes of hyperammonaemia with an episode survival rate of 96%. The survival rate for neonatal crises was 73% and for postneonatal crises it was 98%. Among 93 children over the age of 11 years there were 437 episodes and the episode survival rate was 99%. The likelihood of survival decreased with rising blood ammonium concentrations but nearly all patients with a maximum concentration of 500 μmol/l or less survived. Among patients who were comatose on admission the survival rate was 81%. Among neonates with a maximum blood ammonium concentration >1000 μmol/, the rate of survival was only 38%. Adverse events including cerebral oedema were documented in over half of treated patients. Dialysis was used in 56 neonates and 80 older patients. Overdosage with phenylacetate and benzoate was documented in 13 cases and was fairly frequent during fatal episodes. Clear prescriptions and checking of doses are important and this treatment may be contraindicated in the presence of liver or kidney failure.
These survival rates contrast with neonatal and postneonatal survival rates of 16% and 72% reported in 2005 for patients not given alternative‐pathway treatment. More long‐term data about neurological outcomes are needed.