Genetics of Hyperammonemia Workup
- Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD more...
Plasma ammonia level
Obtain this measurement when clinical signs and symptoms are suggestive of hyperammonemia. Especially in the newborn, symptoms and signs suggestive of sepsis must always be accompanied by a plasma ammonia measurement, since the distinction between the two entities cannot be made by any clinical means and the presence of one does not preclude the other, in any case.
No other laboratory test can substitute for this measurement, nor does any other test indicate need for it.
Only clinical suspicion indicates need.
Liver function studies (ie, serum transaminases, prothrombin time [PT]/activated partial thromboplastin time [aPTT]), alkaline phosphatase levels, bilirubin levels)
Severe liver disease can cause hyperammonemia; therefore, evaluating the function of the liver is always appropriate as a first approximation to etiology.
Plasma amino acid level quantitation
Certain primary genetic causes can be suspected based on specific increases in amino acid levels, such as increased citrulline or argininosuccinic acid levels.
By contrast, severe liver disease tends to cause a generalized increase in plasma amino acid levels.
Urinary organic acid profile
Disorders that involve metabolic intermediates of amino acid catabolism can cause mild-to-moderate inhibition of the urea cycle, resulting in hyperammonemia as a secondary phenomenon.
This test can help to identify level increases in such intermediates as propionic acid, methylmalonic acid, isovaleric acid, or other organic acids and aid in diagnosis.
Urine amino acid levels
These are helpful in confirming argininosuccinic aciduria; lysinuric protein intolerance; or hyperornithinemia, hyperammonemia, and homocitrullinuria (HHH) syndrome.
Blood lactate levels
This is useful in ruling out mitochondrial diseases.
Blood gas levels
Patients with urea cycle disorders may have alkalosis due to stimulation of the respiratory drive by ammonia.
Patients with urea cycle disorders are rarely acidotic. Severe refractory acidosis suggests organic acid disorder or mitochondrial disorder.
This is often very low (< 3 mg of urea/100 mL) in persons with urea cycle disorders.
In infants with confirmed hyperammonemia, oral loading with N -carbamoyl-L-glutamic acid has been advocated as both diagnostic and therapeutic for patients with N -acetylglutamate (NAG) synthetase deficiency.
Some authors advocate baseline MRI studies in patients with confirmed genetic causes of hyperammonemia; this is because some suggestive data indicate an elevated risk for stroke in these patients.
Bosoi CR, Rose CF. Identifying the direct effects of ammonia on the brain. Metab Brain Dis. 2009 Mar. 24(1):95-102. [Medline].
Eefsen M, Jelnes P, Schmidt LE, et al. Brain expression of the water channels aquaporin-1 and -4 in mice with acute liver injury, hyperammonemia and brain edema. Metab Brain Dis. 2010 Sep. 25(3):315-23. [Medline].
Lichter-Konecki U, Mangin JM, Gordish-Dressman H, Hoffman EP, Gallo V. Gene expression profiling of astrocytes from hyperammonemic mice reveals altered pathways for water and potassium homeostasis in vivo. Glia. 2008 Mar. 56(4):365-77. [Medline].
Summar ML, Koelker S, Freedenberg D, et al. The incidence of urea cycle disorders. Mol Genet Metab. Sept-Oct/2013. 110:179-180. [Medline].
Lindner M, Gramer G, Haege G, Fang-Hoffmann J, Schwab KO, Tacke U, et al. Efficacy and outcome of expanded newborn screening for metabolic diseases--report of 10 years from South-West Germany. Orphanet J Rare Dis. 2011 Jun 20. 6:44. [Medline]. [Full Text].
Haeberle J, Boddaert N, Burlina A, et al. Suggested guidelines for the diagnosis and management of urea cycle disorders. Orphanet J Rare Dis. May/2012. 7:1750-1172. [Medline].
Summar ML, Dobbelaere D, Brusilow S, Lee B. Diagnosis, symptoms, frequency and mortality of 260 patients with urea cycle disorders from a 21-year, multicentre study of acute hyperammonaemic episodes. Acta Paediatr. 2008 Oct. 97(10):1420-5. [Medline]. [Full Text].
Kasahara M, Sakamoto S, Horikawa R, et al. Living donor liver transplantation for pediatric patients with metabolic disorders: the Japanese multicenter registry. Pediatr Transplant. Feb/2014. 18:6-15. [Medline].
Perito ER, Rhee S, Roberts JP, et al. Pediatric liver transplantion for urea cycle disorders and organic acidemias: United Network for Organ Sharing data for 2002-2012. Liver Transpl. Jan/2014. 20:89-99. [Medline].
Meyburg J, Das AM, Hoerster F, et al. One liver for four children: first clinical series of liver cell transplantation for severe neonatal urea cycle defects. Transplantation. 2009 Mar 15. 87(5):636-41. [Medline].
Albrecht J. Roles of neuroactive amino acids in ammonia neurotoxicity. J Neurosci Res. 1998 Jan 15. 51(2):133-8. [Medline].
Bachmann C. Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation. Eur J Pediatr. 2003 Jun. 162(6):410-6. [Medline].
Bachmann C, Braissant O, Villard AM, Boulat O, Henry H. Ammonia toxicity to the brain and creatine. Mol Genet Metab. 2004 Apr. 81 Suppl 1:S52-7. [Medline].
Belanger-Quintana A, Martinez-Pardo M, Garcia MJ, et al. Hyperammonaemia as a cause of psychosis in an adolescent. Eur J Pediatr. 2003 Nov. 162(11):773-5. [Medline].
Berry GT, Steiner RD. Long-term management of patients with urea cycle disorders. J Pediatr. 2001 Jan. 138(1 Suppl):S56-60; discussion S60-1. [Medline].
Cohn RM, Roth KS. Hyperammonemia, bane of the brain. Clin Pediatr (Phila). 2004 Oct. 43(8):683-9. [Medline].
Faqiuoli S, Daina E, D'Antiga L, et al. Monogenic diseases that can be cured by liver transplantation. J Hepatol. Sept/2013. 59:595-612. [Medline].
Felipo V, Hermenegildo C, Montoliu C, Llansola M, Minana MD. Neurotoxicity of ammonia and glutamate: molecular mechanisms and prevention. Neurotoxicology. 1998 Aug-Oct. 19(4-5):675-81. [Medline].
Felipo V, Kosenko E, Minana MD, Marcaida G, Grisolia S. Molecular mechanism of acute ammonia toxicity and of its prevention by L-carnitine. Adv Exp Med Biol. 1994. 368:65-77. [Medline].
Guffon N, Schiff M, Cheillan D, et al. Neonatal hyperammonemia: the N-carbamoyl-L-glutamic acid test. J Pediatr. 2005 Aug. 147(2):260-2. [Medline].
Jackson MJ, Beaudet AL, O'Brien WE. Mammalian urea cycle enzymes. Annu Rev Genet. 1986. 20:431-64. [Medline].
Kosenko E, Kaminski Y, Lopata O, Muravyov N, Felipo V. Blocking NMDA receptors prevents the oxidative stress induced by acute ammonia intoxication. Free Radic Biol Med. 1999 Jun. 26(11-12):1369-74. [Medline].
Marcaida G, Felipo V, Hermenegildo C, Minana MD, Grisolia S. Acute ammonia toxicity is mediated by the NMDA type of glutamate receptors. FEBS Lett. 1992 Jan 13. 296(1):67-8. [Medline].
McBride KL, Miller G, Carter S, et al. Developmental outcomes with early orthotopic liver transplantation for infants with neonatal-onset urea cycle defects and a female patient with late-onset ornithine transcarbamylase deficiency. Pediatrics. 2004 Oct. 114(4):e523-6. [Medline].
Miga DE, Roth KS. Hyperammonemia: the silent killer. South Med J. 1993 Jul. 86(7):742-7. [Medline].
Norenberg MD. Astroglial dysfunction in hepatic encephalopathy. Metab Brain Dis. 1998 Dec. 13(4):319-35. [Medline].
Norenberg MD, Rama Rao KV, Jayakumar AR. Ammonia neurotoxicity and the mitochondrial permeability transition. J Bioenerg Biomembr. 2004 Aug. 36(4):303-7. [Medline].
Ott P, Clemmesen O, Larsen FS. Cerebral metabolic disturbances in the brain during acute liver failure: from hyperammonemia to energy failure and proteolysis. Neurochem Int. 2005 Jul. 47(1-2):13-8. [Medline].
Rama Rao KV, Jayakumar AR, Norenberg DM. Ammonia neurotoxicity: role of the mitochondrial permeability transition. Metab Brain Dis. 2003 Jun. 18(2):113-27. [Medline].
Riordan SM, Williams R. Treatment of hepatic encephalopathy. N Engl J Med. 1997 Aug 14. 337(7):473-9. [Medline].
Snyder MJ, Bradford WD, Kishnani PS, Hale LP. Idiopathic hyperammonemia following an unrelated cord blood transplant for mucopolysaccharidosis I. Pediatr Dev Pathol. 2003 Jan-Feb. 6(1):78-83. [Medline].
Steiner RD, Cederbaum SD. Laboratory evaluation of urea cycle disorders. J Pediatr. 2001 Jan. 138(1 Pt 2):S21-S29. [Medline].
Tofteng F, Hauerberg J, Hansen BA, et al. Persistent arterial hyperammonemia increases the concentration of glutamine and alanine in the brain and correlates with intracranial pressure in patients with fulminant hepatic failure. J Cereb Blood Flow Metab. 2006 Jan. 26(1):21-7. [Medline].
Inoue K, Takahashi T, Yamamoto Y, et al. Influence of glutamine synthetase gene polymorphisms on the development of hyperammonemia during valproic acid-based therapy. Seizure. Dec 2015. 33:76-80. [Medline].
Opladen T, Lindner M, Das AM, et al. In vivo monitoring of urea cycle activity with (13)C-acetate as a tracer of ureagenesis. Mol Genet Metab. Jan 2016. 117:19-26. [Medline].
Koelker S, Garcia-Cazorla A, Valayannopoulos V, et al. The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation. J Inherit Metab Dis. Nov 2015. 38:1041-1057. [Medline].
Batshaw ML, Tuchman M, Summar M, et al. A longitudinal study of urea cycle disorders. Mol Genet Metab. Sept-Oct 2014. 113:127-130. [Medline].