Skip to main content

Advertisement

SpringerLink
Log in

Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N-acetylglutamate synthase deficiency

  • Original Paper
  • Published:
European Journal of Pediatrics Aims and scope Submit manuscript

Abstract

Introduction

N-Acetylglutamate synthase (NAGS) deficiency is a rare urea cycle disorder, which may present in the neonatal period with severe hyperammonemia and marked neurological impairment.

Case report

We report on a Turkish family with a patient who died due to hyperammonemia in the neonatal period. Reduced activity of NAGS and carbamyl phosphate synthetase were found at autopsy. A second child who developed hyperammonemia on the second day of life was immediately treated with arginine hydrochloride, sodium benzoate and protein restriction. After NAGS deficiency was suspected by enzyme analysis, sodium benzoate was replaced by N-carbamylglutamate (NCG). A third child who developed slight hyperammonemia on the third day of life was treated with NCG before enzyme analysis confirmed reduced NAGS activity. Neither of the patients developed hyperammonemia in the following years. After the human NAGS gene was identified, mutation analysis revealed that the older sibling on NCG therapy was homozygous for a 971G>A (W324X) mutation. The parents and the younger sibling were heterozygous. Therapy was continued in the older sibling until now without any adverse effects and favourable neurodevelopment outcome. In the younger sibling, therapy was stopped without any deterioration of urea cycle function.

Conclusion

NAGS deficiency can be successfully treated with NCG and arginine hydrochloride with favourable outcome. Molecular diagnostic rather than enzyme analysis should be used in patients with suspected NAGS deficiency.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

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

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

Abbreviations

NAG:

N-Acetylglutamate

NCG:

N-Carbamylglutamate

NAGS:

N-Acetylglutamte synthase

CPSI:

Carbamylglutamate synthetase 1

OTC:

Ornithine transcarbamylase

References

  1. Batshaw ML, MacArthur RB, Tuchman M (2001) Alternative pathway therapy for urea cycle disorders: twenty years later. J Pediatr 138:S46–S55. doi:10.1067/mpd.2001.111836

    Article  CAS  PubMed  Google Scholar 

  2. Brusilow SW, Horwich AL (2001) Urea cycle enzymes. In: Scriver CR, Beaudet AL, Sly WS, Valle D (eds) The metabolic and molecular bases of inherited disease, 8th edn. McGraw-Hill, New York, pp 1909–1963

    Google Scholar 

  3. Caldovic L, Morizono H, Daikhin Y et al (2004) Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate. J Pediatr 145:552–554. doi:10.1016/j.jpeds.2004.06.047

    Article  CAS  PubMed  Google Scholar 

  4. Caldovic L, Morizono H, Tuchman M (2007) Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. Hum Mutat 28:754–759. doi:10.1002/humu.20518

    Article  CAS  PubMed  Google Scholar 

  5. Colombo JP, Krähenbühl S, Bachmann C, Aeberhard P (1982) N-Acetylglutamate synthetase: enzyme assay in human liver. J Clin Chem Clin Biochem 20:325–229

    CAS  PubMed  Google Scholar 

  6. Enns GM, Berry SA, Berry GT et al (2007) Survival after treatment with phenylacetate and benzoate for urea-cycle disorders. N Engl J Med 356:2282–2292. doi:10.1056/NEJMoa066596

    Article  CAS  PubMed  Google Scholar 

  7. Guffon N, Vianey-Saban C, Bourgeois J et al (1995) A new neonatal case of N-acetylglutamate synthase deficiency treated by carbamylglutamate. J Inherit Metab Dis 18:61–65. doi:10.1007/BF00711374

    Article  CAS  PubMed  Google Scholar 

  8. Häberle J, Schmidt E, Pauli S et al (2003) Mutation analysis in patients with N-acetylglutamate synthase deficiency. Hum Mutat 21:593–597. doi:10.1002/humu.10216

    Article  PubMed  Google Scholar 

  9. Hall LM, Metzenberg RL, Cohen PP (1958) Isolation and characterization of a naturally occurring cofactor of carbamyl phosphate biosynthesis. J Biol Chem 230:1013–1021

    CAS  PubMed  Google Scholar 

  10. Heckmann M, Wermuth B, Häberle J et al (2005) Misleading diagnosis of partial N-acetylglutamate synthase deficiency based on enzyme measurement corrected by mutation analysis. Acta Paediatr 94:121–124. doi:10.1080/08035250410030937

    Article  CAS  PubMed  Google Scholar 

  11. Hinnie J, Colombo JP, Wermuth B, Dryburgh FJ (1997) N-Acetylglutamate synthetase deficiency responding to carbamylglutamate. J Inherit Metab Dis 20:839–840. doi:10.1023/A:1005344507536

    Article  CAS  PubMed  Google Scholar 

  12. Plecko B, Erwa W, Wermuth B (1998) Partial N-acetylglutamate synthetase deficiency in a 13-year-old girl: diagnosis and response to treatment with N-carbamylglutamate. Eur J Pediatr 157:996–998. doi:10.1007/s004310050985

    Article  CAS  PubMed  Google Scholar 

  13. Rubio V, Grisolía S (1981) Treating urea cycle defects. Nature 292:496. doi:10.1038/292496a0

    Article  CAS  PubMed  Google Scholar 

  14. Schubiger G, Bachmann C, Barben P et al (1991) N-Acetylglutamate synthetase deficiency: diagnosis, management and follow-up of a rare disorder of ammonia detoxication. Eur J Pediatr 150:353–356. doi:10.1007/BF01955939

    Article  CAS  PubMed  Google Scholar 

  15. Tuchman M, Caldovic L, Daikhin Y et al (2008) N-Carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers. Pediatr Res 64:213–217. doi:10.1203/PDR.0b013e318179454b

    Article  CAS  PubMed  Google Scholar 

Download references

Conflict of interest

The authors declare no conflict of interest. The work was not sponsored and there is no financial relationship.

Author information

Authors and Affiliations

  1. Klinikum, Klinik für Kinder und Jugendliche, 78461, Konstanz, Germany

    Peter Gessler & Hans U. Schwenk

  2. Klinikum, Apotheke, 78461, Konstanz, Germany

    Peter Buchal

  3. Inselspital, Universitätsinstitut für Klinische Chemie, 3010, Bern, Switzerland

    Bendicht Wermuth

Authors
  1. Peter Gessler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Peter Buchal
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hans U. Schwenk
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Bendicht Wermuth
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter Gessler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Gessler, P., Buchal, P., Schwenk, H.U. et al. Favourable long-term outcome after immediate treatment of neonatal hyperammonemia due to N-acetylglutamate synthase deficiency. Eur J Pediatr 169, 197–199 (2010). https://doi.org/10.1007/s00431-009-1006-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00431-009-1006-0

Keywords

Search

Navigation