Diagnosis and Management of Hyperammonemia in Newborns: Is It Still a Challenge?

Document Type : Original Article


1 Division of Pediatric Metabolic Diseases, Department of Pediatrics, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey

2 Division of Neonatology, Department of Pediatrics, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey

3 Department of Pediatrics, Bakirkoy Dr. Sadi Konuk Training and Research Hospital, University of Health Sciences, Istanbul, Turkey


Background: Hyperammonaemia is a serious cause of mortality and morbidity duringin the neonatal period, regardless of the aetiology. Quickly differentiatingon between inherited metabolic diseases (IMDs) and other causes is important in terms of for treatment and prognosis. We This study aimed to determine the diagnostic and prognostic differences between IMD- and non-IMD-related causes with based on a literature review.
Methods: Clinical and laboratory data of newborns treated for hyperammonaemia between 2016 and 2019 were evaluated retrospectively.
Results: Hyperammonaemia was detected in 60 out of 1963 (3%) patients, and 25% of these patients were diagnosed with IMD. The most common non-IMD etiologies were sepsis (31.6%) and prematurity (31.6%). Significant differences were detected between the two groups inregarding gestational age (P=0.001) and birth weight (P=0.005)were detected (p=0.001 and p=0.005, respectively). Moreover, another significant difference was observed between the two groups in terms of glutamine (P=0.004), alanine (P=0.004), and citrulline (P=0.001) levels and as well as the proportions of glutamine to arginine (G/A)P=0.001), citrulline (G/CP=0.0001), ornithine (G/OP=0.003), and alanine (G/A) (P=0.003).
Conclusion: Metabolic screening tests should be performed to rapidly diagnose hyperammonaemia. In addition to the diagnosing diagnosis of IMDs, it can promptly differentiate non-metabolic causes.


  1. Nyhan WL, Kölker S, Hoffman GF. Work-up of the patient with Hyperammonemia. Inherited metabolic diseases. 2nd ed. Berlin Heildelberg: Springer; 2017. P. 113-7.
  2. Haeberle J. Clinical and biochemical aspects
    of primary and secondary hyperammonemic disorders. Arch Biochem Biophys. 2013; 536(2):
  3. Thone JG. Treatment of ure cycle disorders. J Pediatr. 1999; 134(3):255-6.
  4. Burgard P, Kölker S, Haege G, Lindner M, Hoffmann GF. Neonatal mortality and outcome at the end of the first year of life in early onset urea cycle disorders-review and meta-analysis of observational studies published over more than 35 years. J Inherit Metab Dis. 2016; 39(2):219-29.
  5. Unsinn C, Das A, Valayannopoulos V, Thimm E, Beblo S, Burlina A, et al. Clinical course of 63 patients with neonatal onset urea cycle disorders in the years 2001-2013. Orphanet J Rare Dis. 2016; 11(1):116. 
  6. Al-Hassnan ZN, Rashed MS, Al-Dirbashi OY, Patay Z, Rahbeeni Z, Abu-Amero KK. Hyperornithinemia-hyperammonemia-homocitrullinuria syndrome with strokelike imaging presentation: clinical, biochemical and molecular analysis. J Neurol Sci. 2008; 264(1-2):187-94.
  7. Kim SZ, Song WJ, Nyhan WL, Ficicioglu C, Mandell R, Shih VE. Long-term follow-up of four patients affected by HHH syndrome. Clin Chim Acta. 2012; 413(13-14):1151-5.
  8. Zhang MH, Gong JY, Wang JS. Citrin deficiency presenting as acute liver failure in an eight-month-old infant. World J Gastroenterol. 2015; 21(23):
  9. Hayasaka K, Numakura C. Adult-onset type II citrullinemia: current insights and therapy. Appl Clin Genet. 2018; 11:163-70.

10. Baumgartner MR, Höster F, Dionisi-Vici C, Haliloglu G, Karall D, Chapman KA, et al. Proposed
guidelines for  the diagnosisand management of methylmalonic and propionic acidemia. Orphanet J Rare Dis. 2014; 9:130.

11. Häberle J, Chakrapani A, Mew NA, Longo N. Hyperammonaemia in classic organic acidaemias: a review of the literature and two case histories. Orphanet J Rare Dis. 2018; 13(1):219.

12. Naylor EW, Chace DH. Automated tandem mass spectrometry for mass newborn screening for disorders in fatty acid, organic acid, and amino acid metabolism. J Child Neurol. 1999; 14(Suppl 1):S4-8.

13. Limketkai BN, Zucker SD. Hyperammonemic encephalopathy caused by carnitine deficiency. J Gen Interm Med. 2008; 23(2):210-3.

14. Spodenkiewicz M, Diez-Fernandez C, Rüfenacht V, Gemperle-Britschgi C, Häberle J. Minireview on glutamine synthetase deficiency, an ultra-rare ınborn error of amino acid biosynthesis. Biology. 2016; 5(4):40.

15. Mori M, Mytinger JR, Martin LC, Bartholomew D, Hickeym S. 8993T>G-associated leigh syndrome with hypocitrullinemia on newborn screening. JIMD Rep. 2014; 17:47-51.

16. Morton SU, Neilan EG, Peake RWA, Shi J, Schmitz-Abe K. Towne M, et al. Hyperammonemia as a presenting feature in two siblings with FBXL4 variants. JIMD Rep. 2017; 35:7-15.

17. Mauhin W, Habarou F, Gobin S, Servais A, Brassier A, Grisel C, et al. Update on lysinuric protein ıntolerance, a multi-faceted disease retrospective cohort analysis from birth to adulthood. Orphanet J Rare Dis. 2017; 12(1):3.

18. Bharat A, Cunningham SA, Scott Budinger GR, Kreisel D, DeWet CJ, Gelman AE, et al. Disseminated Ureaplasma infection as a cause of fatal hyperammonemia in humans. Sci Transl Med. 2015; 7(284):284re3.

19. Kenzaka T, Kato K, Kitao A, Kosami K, Minami K, Yahata S, et al. Hyperammonemia in urinary tract ınfections. PLoS One. 2015; 10(8):e0136220.

20. McEwan P, Simpson D, Kirk JM, Barr DG, McKenzie KJ. Short report: Hyperammonaemia in critically ill septic infants. Arch Dis Child. 2001; 84(6):512-3.

21. Horslen S. Phenotypes of liver diseases in ınfants, children, and adolescents. Dis Liver Child. 2013; 23:107-31.

22. Khalessi N, Khosravi N, Mirjafari M, Afsharkhas L. Plasma ammonia levels in newborns with asphyxia. Iran J Child Neurol. 2016; 10(1):42-6.

23. Maldonado C, Guevara N, Silveira A, Fagiolino P, Va´zquez M. L-Carnitine supplementation to reverse hyperammonemia in a patient undergoing chronic valproic acid treatment: a case report. J Int Med Res. 2017; 45:1268-72.

24. Ling P, Lee DJ, Yoshida EM, Sirrs S. Carnitine deficiency presenting with encephalopathy and hyperammonemia in a patient receiving chronic enteral tube feeding: a case report. J Med Case Rep. 2012; 6:227.

25. Hay WW Jr. Aggressive nutrition of the preterm infant. Curr Pediatr Rep. 2013; 1(4):10.

26. Papamichail M, Pizanias M, Heaton N. Congenital portosystemic venous shunt. Eur J Pediatr. 2018; 177(3):285-94.

27. Vergano SA, Crossette JM, Cusick FC, Desai
BR, Deardorff MA, Sondheimer N. Improving surveillance for hyperammonemia in the newborn. Mol Genet Metab. 2013; 110(1-2):102-5.

28. Poeppelman RS, Tobias JD. Patent ductus venosus and congenital heart disease: a case report and review. Cardiol Res. 2018; 9(5):330-3.

29. van Karnebeek CD, Sly WS, Ross CJ, Salvarinova R, Yaplito-Lee J, Santra S, et al. Mitochondrial carbonic anhydrase VA deficiency resulting from CA5A alterations presents with hyperammonemia in early childhood. Am J Hum Genet. 2014; 94(3):453-61.

30. Donn SM, Banagale RC. Neonatal hyperammonemia. Pediatr Rev. 1984; 5(7):195-202.

31. Kido J, Nakamura K, Mitsubuchi H, Ohura T, Takayanagi M, Matsuo M, et al. Long-term outcome and intervention of urea cycle disorders in Japan. J Inherit Metab Dis. 2012; 35(5):777-85.

32. Ah Mew N, Krivitzky L, McCarter R, Batshaw M, Tuchman M; Urea Cycle Disorders Consortium of the Rare Diseases Clinical Research Network. Clinical outcomes of neonatal onset proximal versus distal urea cycle disorders do not differ. J Pediatr. 2013; 162(2):324-9.e1.  

33. Clay AS, Hainline BE. Hyperammonemia in the ICU. Chest. 2007; 132(4):1368-78.

34. Hudak ML, Jones MD Jr, Brusilow SW. Differentiation of transient hyperammonemia of the newborn and urea cycle enzyme defects by clinical presentation. J Pediatr. 1985; 107(5):712-9. 

35. Tuchman M, Georgieff MK. Transient hyperam-monemia of the newborn: a vascular complication of prematurity? J Perinatol. 1992; 12(3):234-6.

36. Ballard RA, Vinocur B, Reynolds JW. Transient hyperammonemia of the preterm infant. N Engl J Med. 1978; 299(17):920-5. 

37. Felig DM, Brusilow SW, Boyer JL. Hyperammonemic coma due to parenteral nutrition in a woman with heterozygous ornithine transcarbamylase deficiency. Gastroenterology. 1995; 109(1):282-4.

38. Ogul H, Bayraktutan U, Yildirim OS, Suma S, Ozgokce M, Okur A, et al. Magnetic resonance arthrography of the glenohumeral joint: ultrasonography-guided technique using a posterior approach. Eurasian J Med. 2012; 44(2):73-8.

39. van Straten G, van Steenbeek FG, Grinwis GC, Favier RP, Kummeling A, van Gils IH, et al. Aberrant expression and distribution of enzymes of the urea cycle and other ammonia metabolizing pathways in dogs with congenital portosystemic shunts. PLoS One. 2014; 9(6):e100077.

40. Bachmann C. Inherited hyperammonemias. In: Blau N, Duran M, Blaskovic ME, Gibson KM, editors. Physicians guide to the laboratory diagnosis of metabolic diseases. Berlin, Heidelberg: Springer; 2003. P. 261-76.