Genetics of Hyperammonemia
- Author: Karl S Roth, MD; Chief Editor: Maria Descartes, MD more...
Hyperammonemia is not a true disease; it is a sign that specific abnormalities that cause blood ammonia levels to become elevated may be present. Elevated blood ammonia levels cause a constellation of signs and symptoms that may appear to be a single disease.
Normal blood ammonia levels range from 10-40 µmol/L, compared with a BUN level of 6-20 mg/dL. The total soluble ammonia level in a healthy adult with 5 L of circulating blood is only 150 mcg, in contrast to approximately 1000 mg of urea nitrogen present. Because urea is the end product of ammonia metabolism, the disparity in blood quantities of the substrate and product illustrates the following 2 principles:
The CNS is protected from the toxic effects of free ammonia.
The metabolic conversion system that leads to production of urea is highly efficient.
An individual is unlikely to become hyperammonemic unless the conversion system is impaired in some way. In newborns, this impairment is often the result of genetic defects, whereas, in older individuals, the impairment is more often the consequence of a diseased liver. However, a growing number of reports address adult-onset genetic disorders of the urea cycle in previously healthy individuals.
The true mechanism of neurotoxicity in hyperammonemia is not yet fully determined. Irrespective of the underlying cause, the clinical picture is relatively constant. This implies that the pathophysiologic mechanism, focusing on the CNS, is common to all individuals with hyperammonemia.
The normal process of removing the amino group present on all amino acids produces ammonia. The α -amino group is a catabolic key that protects amino acids from oxidative breakdown. Removing the α -amino group is essential for producing energy from any amino acid.
Under normal circumstances, both the liver and the brain generate ammonia in this removal process, substantially contributing to total body ammonia production. The urea cycle is completed in the liver, where urea is generated from free ammonia.
The hepatic urea cycle (see the image below) is the major route for disposal of waste nitrogen chiefly generated from protein and amino acid metabolism.
In the same context, low-level synthesis of certain cycle intermediates in extrahepatic tissues also makes a small contribution to waste nitrogen disposal. Two moles of waste nitrogen are eliminated with each mole of urea excreted. A portion of the cycle is mitochondrial in nature; mitochondrial dysfunction, whether genetically or pharmacologically induced, may impair urea production and result in hyperammonemia. Overall, activity of the cycle is regulated by the rate of synthesis of N -acetylglutamate (NAG), the enzyme activator that initiates incorporation of ammonia into the cycle.
The brain must expend energy to detoxify and to export the ammonia it produces. This is accomplished in the process of producing adenosine diphosphate (ADP) from ATP by the enzyme glutamine synthetase, which is responsible for mediating the formation of glutamine from an amino group. Synthesis of glutamine also reduces the total free ammonia level circulating in the blood; therefore, a significant increase in blood glutamine concentration can signal hyperammonemia.
The biologic requirement for tight regulation is satisfied because the capacity of the hepatic urea cycle exceeds the normal rates of ammonia generation in the periphery and transfer into the blood. Hyperammonemia never results from endogenous production in a state of health.
An elevated blood ammonia level, although it may be secondary, must never be ignored. Moreover, since the normal ureagenic capacity of the liver is so great in relation to physiologic load, such a finding points directly to an impairment of the urea cycle in the liver.
The CNS is most sensitive to the toxic effects of ammonia. Many metabolic derangements occur as a consequence of high ammonia levels, including alteration of the metabolism of important compounds, such as pyruvate, lactate, glycogen, and glucose. High ammonia levels also induce changes in N -methyl D-aspartate (NMDA) and gamma-aminobutyric acid (GABA) receptors and causes downregulation in astroglial glutamate transporter molecules.
As ammonia exceeds normal concentration, an increased disturbance of neurotransmission and synthesis of both GABA and glutamine occurs in the CNS. A correlation between arterial ammonia concentration and brain glutamine content in humans has been described. Moreover, brain content of glutamine is correlated with intracranial pressure. In vitro data also suggest that direct glutamine application to astrocytes in culture causes free radical production and induces the membrane permeability transition phenomenon, which leads to ionic gradient dissipation and consequent mitochondrial dysfunction.
Studies in mice suggest that increased ammonia concentration in brain causes upregulation of aquaporin-4, a water channel which has been associated with increased water permeability in other neurodisorders.[2, 3] However, the true mechanism for neurotoxicity of ammonia is not yet completely defined. The pathophysiology of hyperammonemia is that of a CNS toxin that causes irritability, somnolence, vomiting, cerebral edema, and coma that leads to death.
The frequency of each genetic cause of hyperammonemia is undetermined because of the technical difficulties in accurately detecting each through an organized newborn screening program. The reported incidence of argininosuccinic acid synthase and argininosuccinic acid lyase deficiencies from a database of more than 6 million live births across the United States is 1 per 35,000 live births per year. The combined incidence of urea cycle disorders has been estimated at approximately 1 per 20,000-25,000 live births. Providing incidence figures for clinically significant partial defects or secondary causes of hyperammonemia is not possible. Any severe impairment of liver function, whether temporary or permanent, can initiate the onset of hepatic encephalopathy.
A report from a single screening site in Germany, analyzing samples from almost 1.1 million newborns over a decade, detected a combined total of 11 cases of citrullinemia and argininosuccinic aciduria. A second report indicates that the European incidence of all urea cycle disorders is in the range of 1:8000, a figure difficult to confirm through mass screening because of the aforementioned technical problems.
Progressive hyperammonemia, whether treated or not, eventually causes cerebral edema, coma, and death. A rapid diagnostic evaluation and alleviation of the cause must be accompanied by treatment.
Although the vast majority of morbidity associated with hyperammonemia derives from the primary cause, such as chronic liver disease, repeated hyperammonemic episodes can also cause morbidity. The result, given the direct toxicity of ammonia on the CNS, is a progressive decrease in intellectual function. Animal studies suggest actual cell death as the cause.
In the genetic forms of hyperammonemia, men and women are affected equally because almost all types are autosomal recessive traits. The only exception to equal sex distribution is X-linked ornithine transcarbamylase (OTC) deficiency, the most common of the urea cycle disorders. OTC deficiency predominantly affects males, although female carriers have been clinically affected.
Acquired causes are distributed randomly between the sexes. However, some acquired causes, such as alcoholic cirrhosis, show a population distribution skewed by societal phenomena.
Genetic causes of hyperammonemia manifest as a wide variety of conditions. The different presentations are categorized as catastrophic newborn, late-infantile, and adult. Each inherited disorder is reported in various clinical presentations. In some patients with adult-onset disease, no precedent sign of intellectual dysfunction was present, leading to the assumption that the disorder was truly latent until the first acute presentation.
Age of onset depends on the age and rate of progression of the underlying disease process. Impairments that must be considered range from hepatic necrosis with hepatocellular damage to inborn genetic disorders of the urea cycle. Although history and age of the patient are helpful to diagnosis, genetic causes must never be disregarded, irrespective of the stage of life. Data from a very large cohort of patients (260) with inherited urea cycle disorders showed a surprisingly high rate of initial onset beyond the neonatal period (66%). Indeed, in a subgroup of 69 males with OTC deficiency, 35% presented when older than 2 years in this series.
In general, it is difficult to determine the prognosis for an individual with hyperammonemia. The extent of lasting damage done by a single episode of hyperammonemia may be trivial if the episode is mild and short-lived, whereas such situations, if repetitive, can cause extensive and permanent dysfunction. Likewise, a single occasion of severe hyperammonemia may cause irreversible damage and/or death. Age at onset is also an important factor in determination of likely recovery.
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].