Treatment of urea cycle disorders  

Oleh:

Thoene, Jess G.

Jenis: Article from Journal - ilmiah internasional
Dalam koleksi: The Journal of Pediatrics vol. 134 no. 3 (Mar. 1999), page 255-256 .
Topik: OTC ; Ornithine transcarbamylase

Ketersediaan

Perpustakaan FK Nomor Panggil: J45.K Non-tandon: 1 (dapat dipinjam: 0) Tandon: tidak ada

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The problem of disposal of waste nitrogen produced as a byproduct of protein catabolism has been nicely solved in ureotelic organisms by the urea cycle. Two moles of ammonia are excreted as 1 mole of urea per turn of the 5-step cycle, at a net cost of 3 moles of adenosine triphosphate. Urea is nontoxic and water-soluble and has a high renal clearance, thus making it an ideal inert end product.1 Interruption of the cycle by a mutation at 1 of the 4 loci coding for an enzyme involved in the first 4 steps of urea synthesis ablates the function of the cycle, leading to protein intolerance, hyperammonemia, lethargy, coma, and death. Urea cycle disorders were first described in the early 1960s,2, 3 but the diagnosis was difficult and infrequent, and effective therapy for the severe forms of these conditions was nonexistent. Five of the first 7 patients reported with citrullinemia, a defect in the third step of the cycle, died at less than 1 week of age.4 Those who survived the neonatal period were profoundly retarded. With the advent of alternative means of waste nitrogen disposition developed by Brusilow et al,1 these children began to have an improved prognosis. First with ketoacids4, 5 and subsequently with a combination of sodium benzoate and phenylacetate (Ucephan), the outlook for patients with ornithine transcarbamylase deficiency and related urea cycle disorders began to change from one of certain death in the first weeks of life to one of prolonged survival and acquisition of cognitive function. New Drug Approval for Ucephan occurred in 1987, and subsequently an improved, less odorous form (sodium phenylbutyrate) was approved as Buphenyl by the Food and Drug Administration in 1996. This pharmacologic improvement made the administration of the drug much more acceptable for patient and parents alike.1 However, initial treatment and treatment of intercurrent episodes of hyperammonemia remained among the most taxing in pediatric medicine. As alternative means of acute ammonia disposition improved (these drugs plus hemodialysis, hemofiltration, etc), so the potential for survival of a given episode improved in parallel. Addition of sodium phenylbutyrate and either arginine or citrulline, depending on the specific disorder in question, allowed these children to attend school and make developmental progress with some semblance of a normal life. Nevertheless, intercurrent episodes of hyperammonemia, frequently attendant on an intercurrent viral infection, remain a constant threat. With age and recurrent episodes of hyperammonemia, developmental milestones and potential for further development are lost. In this issue of The Journal, Maestri, Clissold, and Brusilow6 courageously report the results of long-term treatment of OTC deficiency. The results are clearly not what the developers of these compounds would have hoped; 50% of the children are dead by 4 years of age, and of those surviving, the mean IQ is <50. These results, however, must be compared with the natural history described above. To have children with this lethal condition survive to the age of 10 or 12 years, even developmentally delayed, is a significant advance. Early treatment clearly requires early diagnosis. The authors note that in OTC deficiency, respiratory alkalosis is regularly observed. Many of us have been teaching residents for decades that it is essential to order a metabolic screen and plasma ammonium determination for any catastrophically ill newborn.7 Add to this now the recognition that patients with OTC deficiency have a mean pH of 7.5 and a PCO 2 of 24 as a result of respiratory alkalosis. This finding should alert the staff to trigger the appropriate investigations. The real challenge now is to determine the next step in improving prospects for these children. Administration of the compounds in question can certainly provide intervals free of hyperammonemia episodes, during which the child grows and makes developmental progress. One possibility being explored at several centers is early orthotopic liver transplantation. Gene therapy is also under investigation.8 To the extent that these compounds allow the children to grow until transplantation or gene therapy becomes feasible, the drugs have served a noble purpose. The results reported in the article by Maestri et al6 must be construed as success, not failure.

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