Skip to main content

Alternative pathway therapy for urea cycle disorders

Journal of Inherited Metabolic Disease volume 21, pages 101–111 (1998)Cite this article

Abstract

In man the major pathway for the disposal of waste nitrogen is the urea cycle; in inborn errors of this pathway, nitrogen flux is reduced. As a result there is accumulation of ammonia and glutamine with disordered metabolism of other amino acids. Nitrogen homeostasis can be restored in these patients with a low-protein diet combined with compounds that create alternative pathways for nitrogen excretion. The introduction of these compounds has been a major advance in the management of these inborn errors and as a result the outcome, particularly for those treated early, has improved.

This is a preview of subscription content, access via your institution.

Access options

Buy single article

Instant access to the full article PDF.

USD 39.95

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

REFERENCES

  • Bachmann C, Colombo JP (1983) Incrased tryptophan uptake into the brain in hyperammonaemia. Life Sci 33: 2417–2424.

    Google Scholar 

  • Bachmann C, Lüthi H, Gradwohl M, Colombo JP (1986) Brain uptake of tryptophan in urease-injected hyperammonaemic rats after treatment with benzoate or hippurate. Biochem Med Metab Biol 36: 214–219.

    Google Scholar 

  • Barshop BA, Breuer J, Holm J, Leslie J, Nyhan WL (1989) Excretion of hippuric acid during sodium benzoate therapy in patients with hyperglycinaemia or hyperammonaemia. J Inher Metab Dis 12: 72–79.

    Google Scholar 

  • Batshaw ML (1983) Sodium benzoate and arginine: alternative pathway therapy in inborn errors of urea synthesis. Prog Clin Biol Res 127: 69–83.

    Google Scholar 

  • Batshaw ML, Brusilow SW (1981) Evidence of lack of toxicity of sodium phenylacetate and sodium benzoate in treating urea cycle enzymopathies. J Inher Metab Dis 4: 231.

    Google Scholar 

  • Brusilow SW (1984) Arginine, an indispensable amino acid for patients with inborn errors of urea synthesis. J Clin Invest 74: 2144–2148.

    Google Scholar 

  • Brusilow SW (1991) Phenylacetylglutamine may replace urea as a vehicle for waste nitrogen excretion. Pediatr Res 29: 147–150.

    Google Scholar 

  • Brusilow SW, Batshaw ML (1979) Arginine treatment of argininosuccinase deficiency. Lancet 1: 124–126.

    Google Scholar 

  • Brusilow SW, Horwich AL (1995) Urea cycle enzymes. In. Scriver CR, Beaudet AL, Sly WS, Valle D, eds. The Metabolic and Molecular Bases of Inherited Disease, 7th edn. New York: McGraw-Hill, 1187–1232.

    Google Scholar 

  • Brusilow SW, Maestri NE (1996) Urea cycle disorders: diagnosis, pathophysiology, and therapy. Adv Pediatr 43: 127–170.

    Google Scholar 

  • Brusilow SW, Valle DL, Batshaw M (1979) New pathways of nitrogen excretion in inborn errors of urea synthesis. Lancet 2: 452–454.

    Google Scholar 

  • Connelly A, Cross JH, Gadian DG, Hunter JV, Kirkham FJ, Leonard JV (1993) Magnetic resonance spectroscopy shows increased brain glutamine in ornithine carbamoyl transferase deficiency. Pediatr Res 33: 77–81.

    Google Scholar 

  • Gregus Z, Fekete T, Varga F, Klaassen CD (1992) Availability of glycine and coenzyme A limits glycine conjugation in vivo. Drug Metab Dispos 20: 234–240

    Google Scholar 

  • Griffith AD, Cyr DM, Egan SG, et al (1989) Inhibition of pyruvate carboxylase by sequestration of coenzyme A with sodium benzoate. Arch Biochem Biophys 269: 201–207.

    Google Scholar 

  • Hyman SL, Porter CA, Page TJ, Iwata BA, Kissel R, Batshaw ML (1987) Behavior management of feeding disturbances in urea cycle and organic acid disorders. J Pediatr 111: 558–562.

    Google Scholar 

  • Kalbag SS, Palekar AG (1988) Soidum benzoate inhibits fatty acids oxidation in rat liver. Effect on ammonia levels. Biochem Metab Biol 40: 133–142.

    Google Scholar 

  • Kline JJ, Hug G, Schubert WK, Berry H (1981) Arginine deficiency syndrome. Am J Dis Child 135: 437–442.

    Google Scholar 

  • Kubota K, Ishizaki T (1991) Dose-dependent pharmacokinetics of benzoic acid following oral administration of sodium benzoate to humans. Eur J Clin Pharmacol 41: 363–368.

    Google Scholar 

  • Kubota K, Ishizaki T (1993) Effect of single oral dose of sodium benzoate on ureagenesis in healthy men and two patients with late onset citrullinaemia. Eur J Clin Pharmacol 45: 465–468.

    Google Scholar 

  • Leonard JV (1995) Urea cycle disorders. In Fernandes J, Saudubray JM, Van den Berghe G, eds. Inborn Metabolic Diseases: Diagnosis and Treatment, 2nd ed. Berlin: Springer-Verlag, 167–176.

    Google Scholar 

  • Letarte J, Qureshi IA, Ouellet R, Godard M (1985) Chronic benzoate therapy in a boy with partial ornithine transcarbamylase deficiency. J Pediatr 106: 794–797.

    Google Scholar 

  • Lewis HB (1914) Studies in the synthesis of hippuric acid in the animal organism. J Biol Chem 18: 225–231.

    Google Scholar 

  • Maestri NE, Hauser ER, Bartholomew D, Brusilow SW (1991) Prospective treatment of urea cycle disorders. J Pediatr 119: 923–928.

    Google Scholar 

  • Maestri NE, McGowan KD, Brusilow SW (1992) Plasma glutamine concentration: a guide to the management of urea cycle disorders. J Pediatr 121: 259–261.

    Google Scholar 

  • Maestri NE, Clissold DB, Brusilow SW (1995) Long-term survival of patients with argininosuccinate synthetase deficiency. J Pediatr 127: 929–935.

    Google Scholar 

  • Maestri NE, Brusilow SW, Clissold DB, Bassett SS (1996) Long-term treatment of girls with ornithine transcarbamylase deficiency. N Engl J Med 335: 855–859.

    Google Scholar 

  • Michalak A, Lambert MA, Dallaire L, et al (1990) Hypocarnitinemie chez les patients atteints d'un defaut primaire du metabolisme de l'ammoniaque traites avec le benzoate de sodium. Diabete Metab 16: 226–233.

    Google Scholar 

  • Msall M, Batshaw ML, Suss R, Brusilow SW, Mellits ED (1984) Neurologic outcome in children with inborn errors of urea synthesis. N Engl J Med 310: 1500–1505.

    Google Scholar 

  • O'Connor JE, Costell M, Grisolia S (1987) The potentiation of ammonia toxicity by sodium benzoate is prevented by L-carnitine. Biochem Biophys Res Commun 145: 817–824.

  • O'Connor JE, Costell M, Grisolia S (1989) Carbamyl glutamate prevents the potentiation of ammonia toxicity by sodium benzoate. Eur J Pediatr 148: 540–542.

  • Ohtani Y, Ohyagani K, Yamamoto S, Matsuda I (1988) Secondary carnitine deficiency in hyperammonemic attacks of ornithine transcarbamylase deficiency. J Pediatr 112: 409–414.

    Google Scholar 

  • Palekar AG, Kalbag SS (1991) Amino acids in the rat liver and plasma and some metabolites in the liver after sodium benzoate treatment. Biochem Med Metab Biol 46: 52–58.

    Google Scholar 

  • Piscitelli SC, Thibault A, Figg WD, et al (1995) Disposition of phenylbutyrate and its metabolites, phenylacetate and phenylacetylglutamine. J Clin Pharmacol 35: 368–373.

    Google Scholar 

  • Ratnakumari L, Qureshi IA, Butterworth RF (1993a) Effect of L-carnitine on cerebral and hepatic energy metabolites in congenitally hyperammonemic sparse-fur mice and its role during benzoate therapy. Metabolism 42: 1039–1046.

    Google Scholar 

  • Ratnakumari L, Qureshi IA, Butterworth RF (1993b) Effect of sodium benzoate on cerebral and hepatic energy metabolites in spf mice with congenital hyperammonemia. Biochem Pharmacol 45: 137–146.

    Google Scholar 

  • Simell O, Sipila I, Rajantie J, Valle DL, Brusilow SW (1986) Waste nitrogen excretion via amino acid acylation: benzoate and phenylacetate in lysinuric protein intolerance. Pediatr Res 20: 1117–1121.

    Google Scholar 

  • Snyderman SE, Boyer A, Holt EL (1959) The arginine requirement of the infant Am J Dis Child 97: 192–195.

    Google Scholar 

  • Surtees RJ, Leonard JV (1989) Acute metabolic encephalopathy. J Inher Metab Dis 12(supplement 1): 42–54.

    Google Scholar 

  • Takeda E, Kuroda Y, Toshima K, Watanabe T, Naito E, Miyao M (1983) Effect of long term administration of sodium benzoate to a patient with partial ornithine carbamoyl transferase deficiency. Clin Pediatr Phila 22: 206–208.

    Google Scholar 

  • Tremblay GC, Qureshi IA (1993) The biochemistry and toxicology of benzoic acid metabolism and its relationship to the elimination of waste nitrogen. Pharmac Ther 60: 63–90.

    Google Scholar 

  • Wiech NL, Clissold DM, MacArthur RB (1997) Safety and efficacy of buphenyl (sodium phenylbutyrate) tablets and powder (Abstract). Advances in Inherited Urea Cycle Disorders, Satellite to the 7th International Congress for Inborn Errors of Metabolism, Vienna.

  • Wildham K, Koch S, Scheibenreiter S, et al (1992) Long-term follow-up of 12 patients with late onset variant of argininosuccinic acid lysase deficiency: no impairment of intellectual and psychomotor development during therapy. Pediatrics 89: 1182–1184.

    Google Scholar 

Download references

Authors
  1. F. Feillet
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. V. Leonard
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Feillet, F., Leonard, J.V. Alternative pathway therapy for urea cycle disorders. J Inherit Metab Dis 21 (Suppl 1), 101–111 (1998). https://doi.org/10.1023/A:1005365825875

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1005365825875

Keywords

  • Public Health
  • Nitrogen
  • Ammonia
  • Internal Medicine
  • Urea