Journal of Inherited Metabolic Disease

, Volume 28, Issue 5, pp 651–663

Benzoate treatment and the glycine index in nonketotic hyperglycinaemia

  • J. L. K. Van Hove
  • K. Vande Kerckhove
  • J. B. Hennermann
  • V. Mahieu
  • P. Declercq
  • S. Mertens
  • M. De Becker
  • P. S. Kishnani
  • J. Jaeken
Article

Summary

High-dose benzoate treatment aimed at reducing plasma glycine levels to normal reduces seizures and increases wakefulness in patients with nonketotic hyperglycinaemia (NKH). Since benzoate metabolism is dependent on the available glycine pool, and since the glycine pool is variably affected by the deficiency in the glycine cleavage enzyme system, we examined the importance of interpatient variability in benzoate requirement. To correct for the dietary glycine contribution, the glycine index was introduced as the molar requirement of benzoate dose necessary to normalize plasma glycine levels and subtracting from that the dietary glycine intake, both corrected for weight. The glycine index varied between 3.62 and 4.87 mmol/kg per day in five patients with a poor neurodevelopmental outcome and between 0.92 and 1.90 mmol/kg per day in four patients with a better neurodevelopmental outcome, and was 2.54 mmol/kg per day in a single patient with an intermediate outcome. The glycine index was stable over time within each patient. Exceeding the balance by either increasing food glycine intake or decreasing the benzoate dose resulted in increased glycine levels. Exceeding the glycine tolerance by increasing benzoate resulted in elevated and toxic levels of benzoate. The glycine index is a stable, individually specific parameter in patients with NKH. It has clinical consequences for the dose of benzoate required and the role of dietary management. Through its correlation with neurodevelopmental outcome, the glycine index points to potential genetic factors that could contribute to the psychomotor retardation in NKH.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Aliefendioğlu D, Aslan AT, Coşkun T, Dursun A, Cakmak FN, Kesimer M (2003) Transient nonketotic hyperglycinemia: two case reports and literature review. Pediatr Neurol 28: 151–155.PubMedGoogle Scholar
  2. 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 Inherit Metab Dis 12: 72–79.CrossRefPubMedGoogle Scholar
  3. Batshaw MI, Brusilow S, Waber L, et al (1982) Treatment of inborn errors of urea synthesis: activation of alternative pathways of waste nitrogen synthesis and excretion. N Engl J Med 306: 1387–1392.PubMedCrossRefGoogle Scholar
  4. Bridges JW, French MR, Smith RL, Williams RT (1970) The fate of benzoic acid in various species. Biochem J 118: 47–51.PubMedGoogle Scholar
  5. Cole DEC, Meek DC (1985) Juvenile non-ketotic hyerglycinaemia in three siblings. J Inherit Metab Dis 8(supplement 2): 123–124.PubMedGoogle Scholar
  6. Deutsch SI, Rosse RB, Mastropaolo J (1998) Current status of NMDA antagonist interventions in the treatment of nonketotic hyperglycinemia. Clin Neuropharmacol 21: 71–79.PubMedGoogle Scholar
  7. Dobyns WB (1989) Agenesis of the corpus callosum and gyral malformations are frequent manifestations of nonketotic hyperglycinemia. Neurology 39: 817–820.PubMedGoogle Scholar
  8. 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.PubMedGoogle Scholar
  9. Gregus Z, Fekete T, Varga F, Klaassen CD (1993) Dependence of glycine conjugation on availability of glycine: role of the glycine cleavage system. Xenobiotica 23: 141–153.PubMedCrossRefGoogle Scholar
  10. Gitzelmann R, Steinmann B (1982) NKH Workshop. Clincial and therapeutic aspects of non-ketotic hyperglycinemia. J Inherit Metab Dis 5(supplement 2): 113–116.Google Scholar
  11. Hamosh A, Johnston MV (2001) Nonketotic hyperglycinemia. In: Scriver CR, Beaudet AL, Sly WS, Valle D, eds; Childs B, Kinzler KW, Vogelstein B, assoc. eds. The Metabolic and Molecular Bases of Inherited Disease, 8th edn. New York: McGraw-Hill, 2065–2078.Google Scholar
  12. Hamosh A, Maher JF, Bellus GA, Rasmussen SA, Johnston MV (1998) Long-term use of high-dose benzoate and dextromethorphan for the treatment of nonketotic hyperglycinemia. J Pediatr 132: 709–713.PubMedGoogle Scholar
  13. Heil SG, Van der Put NMJ, Waas ET, den Heijer M, Trijbels FJM, Blom H (2001) Is mutated serine hydroxymethyltransferase (SHMT) involved in the etiology of neural tube defects? Mol Genet Metab 73: 164–172.CrossRefPubMedGoogle Scholar
  14. Hennermann JP, Barufe JM, Monch E (2001) Clinical variation in nonketotic hyperglycinemia. J Inherit Metab Dis 24(supplement 1): 35.Google Scholar
  15. Hoover-Fong JE, Shah S, Van Hove JLK, Applegarth D, Toone J, Hamosh A (2004) Natural history of non-ketotic hyperglycinemia in 65 patients. Neurology 63: 1847–1853.PubMedGoogle Scholar
  16. Krieger I, Winbaum ES, Eisenbray AB (1977) Cerebrospinal fluid glycine in nonketotic hyperglycinemia. Effect of treatment with sodium benzoate and a ventricular shunt. Metabolism 26: 517–524.CrossRefPubMedGoogle Scholar
  17. Kure S, Ichinohe A, Kojima K, et al (2004) Mild variant of nonketotic hyperglycinemia with typical neonatal presentations: mutational and in vitro expression analyses in two patients. J Pediatr 144: 827–829.PubMedGoogle Scholar
  18. MacArthur RB, Altincatal A, Tuchman M (2004) Pharmacokinetics of sodium phenylacetate and sodium benzoate following intravenous administration as both a bolus and continuous infusion to healthy adult volunteers. Mol Genet Metab 81: S67–S73.CrossRefPubMedGoogle Scholar
  19. Palmer T, Oberholzer VG (1985) Amino acid loading tests in a patient with non-ketotic hyperglycinaemia. J Inherit Metab Dis 8(supplement 2): 125–126.PubMedGoogle Scholar
  20. Qureshi I, Rouleau T, Letarte J, Quellet R (1986) Significance of transported glycine in the conjugation of sodium benzoate in spf mutant mice with omithine transcarbamylase deficiency. Biochem Int 12: 839–846.PubMedGoogle Scholar
  21. Qureshi I A, Clermont P, Letarte J (1989) The importance of glyoxylate and other glycine precursors in the hepatic and renal conjugation of benzoate in normal and hyperammonemic mice. Can J Physiol Pharmacol 67: 1426–1430.PubMedGoogle Scholar
  22. Schoovaerts K (2001) De rol van voeding in de behandeling van niet-ketotische hyperglycinemia [The role of nutrition in the treatment of non-ketotic hyperglycinemia]. BSc thesis, KH Leuven.Google Scholar
  23. Shinka T, Inoue Y, Kuhara T, Matsumoto M, Matsumoto I (1985) Benzoylalanine: detection and identification of an alanine conjugate with benzoic acid in hyperammonemic patients treated with sodium benzoate. Clin Chim Acta 151: 293–300.CrossRefPubMedGoogle Scholar
  24. Souci SW, Fachmann W, Kraut H (2000) Food Composition and Nutrition Tables. Stuttgart: Medpharm Scientific Publishers; London: CRC Press.Google Scholar
  25. Steiman GS, Yudkoff M, Berman PH, Blazer-Yost B, Segal S (1979) Late-onset nonketotic hyperglycinemia and spinocerebellar degeneration. J Pediatr 94: 907–911.PubMedGoogle Scholar
  26. Steiner RD, Sweetser DA, Rohrbaugh JR, Dowton SB, Toone JR, Applegarth DA (1996) Nonketotic hyperglycinemia: atypical clinical and biochemical manifestations. J Pediatr 128: 243–246.PubMedGoogle Scholar
  27. Trauner DA, Page T, Greco C, Sweetman L, Kulovich S, Nyhan WL (1981) Progressive neurodegenerative disorder in a patient with nonketotic hyperglycinemia. J Pediatr 98: 272–275.PubMedGoogle Scholar
  28. Trijbels JMF, Monnens LAH, van der Zee SPM, Vrenken JA, Sengers RCA, Schretlen EDA (1974) A patient with nonketotic hyperglycinemia: biochemical findings and therapeutic consequences. Pediatr Res 8: 598–605.PubMedGoogle Scholar
  29. Van Hove JLK, Kishnani P, Muenzer J, et al (1995) Benzoate therapy and carnitine deficiency in non-ketotic hyperglycinemia. Am J Med Genet 59: 444–453.PubMedGoogle Scholar
  30. Van Hove JLK, Kishnani PS, Demaerel P, et al (2000) Acute hydrocephalus in nonketotic hyperglycinemia. Neurology 54: 754–756.PubMedGoogle Scholar
  31. Wolff JA, Kulovich S, Yu AL, Qiao C-N, Nyhan WL (1986) The effectiveness of benzoate in the management of seizures in nonketotic hyperglycinemia. Am J Dis Child 140: 596–602.PubMedGoogle Scholar

Copyright information

© SSIEM and Springer 2005

Authors and Affiliations

  • J. L. K. Van Hove
    • 1
    • 2
    • 7
  • K. Vande Kerckhove
    • 3
  • J. B. Hennermann
    • 4
  • V. Mahieu
    • 1
  • P. Declercq
    • 5
  • S. Mertens
    • 1
  • M. De Becker
    • 1
  • P. S. Kishnani
    • 6
  • J. Jaeken
    • 1
  1. 1.Department of Pediatrics, University Hospital GasthuisbergKatholieke Universiteit LeuvenBelgium
  2. 2.Department of PediatricsUniversity of Colorado Health Sciences CenterDenverUSA
  3. 3.Department of Nutrition, University Hospital GasthuisbergKatholieke Universiteit LeuvenBelgium
  4. 4.Otto-Heubner-Center for Pediatric and Adolescent MedicineCharité University Medical CenterBerlinGermany
  5. 5.Department of Laboratory Medicine, University Hospital GasthuisbergKatholieke Universiteit LeuvenBelgium
  6. 6.Department of Pediatrics, Division of Medical GeneticsDuke University Medical CenterDurhamUSA
  7. 7.Biochemical Genetics LaboratoryUniversity of Colorado Health Sciences Center at FitzsimmonsAuroraUSA

Personalised recommendations