MinireviewCurrent concepts in the pathogenesis of urea cycle disorders
Introduction
Ammonia is produced by intestinal urease-positive bacteria and amino acid metabolism, and is mostly present as ammonium at physiological pH. is maintained at low concentrations (50–150 μM in preterm neonates, 50–75 μM in term neonates, and <50 μM in adults) through conversion of to urea by the urea cycle, for which complete expression occurs in liver exclusively (see [1, and references cited therein]).
Excess of is toxic to the central nervous system (CNS). In adults, liver failure results in hyperammonemia responsible for a potentially severe neuropsychiatric disorder named hepatic encephalopathy, which progressively leads to altered mental status and coma. The symptoms of hepatic encephalopathy in adults can be reversed when concentration returns to normal levels, provided that terminal cerebral edema is not reached. In pediatric patients, hyperammonemia can be caused by various inherited or acquired disorders [2], the most frequent being urea cycle disorders (UCD) with an overall prevalence estimated at 1:8200 in the United States [3], [4]. The developing brain is much more susceptible to the deleterious effects of than the adult brain. Hyperammonemia can provoke irreversible damage to developing CNS, with presentation symptoms such as cognitive impairment, seizures and cerebral palsy [5], [6]. Hyperammonemic neonates and infants develop cortical atrophy, ventricular enlargement, demyelination or gray and white matter hypodensities [4], [6], [7]. The extent of the irreversible damage depends on the maturation of the brain and on the magnitude and duration of exposure. Irreversibility mainly occurs in case of prolonged hyperammonemic crises and/or when blood reaches levels between 200 and 500 μM, during the two first years of life [8], [9], [10], [11], [12]. This review will focus on the most recent advances in understanding the pathogenesis of UCD and ammonium toxicity on the developing CNS.
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Clinical presentation and treatments
Most UCD patients present in the neonatal period with non-specific symptoms (poor feeding, vomiting, somnolence, irritability and tachypnea) [2]. With rise in plasma , symptoms rapidly progress towards hypothermia, lethargy and coma [13]. Hyperammonemia generates edema in CNS, due to astrocyte swelling, which leads to intracranial pressure increase and brain herniation [14], [15]. Neurological problems (seizures, abnormal posture, and neuromuscular irritability) are frequent and depend on
Experimental models to analyze the effects of UCDs on CNS
Apart from the clinical observation of patients with UCD or hepatic encephalopathy, the knowledge on the brain pathogenesis of UCD has been acquired through the use of both in vivo and in vitro experimental systems.
Glutamine
Glutamine synthesis is the major pathway for removal in the brain, by the astrocytic enzyme glutamine synthetase (GS; Fig. 1). Thus, hyperammonemic conditions with high levels of in CNS should increase the synthesis of brain glutamine. Accordingly, a 2- to 3-fold increase in brain glutamine was reported in OTC patients [75] and spf mice [76]. We also showed that NH4Cl exposure of brain cell 3D cultures increases their intracellular concentration of glutamine [77]. Glutamine is an
Conclusion and perspectives
Hyperammonemia during development is associated with neuronal cell loss and cerebral atrophy that lead to mental retardation and cerebral palsy in pediatric patients. In surviving patients suffering from UCD, the pathogenic mechanisms of ammonium toxicity to the brain can involve alterations in amino acids pathways, neurotransmission systems, cerebral energy, nitric oxide synthesis, axonal and dendritic growth, signal transduction pathways or K+ and water channels. These disturbances can lead
Conflict of interest statement
The author declares that there are no conflicts of interest.
Acknowledgments
This work was supported by the Swiss National Science Foundation, Grant Nos. 3100A0-100778 and 3100A0-116859.
References (147)
- et al.
Hyperammonemia-induced toxicity for the developing central nervous system
Brain Res. Rev.
(2007) - et al.
Urea cycle disorders
Semin. Neonatol.
(2002) - et al.
Cross-sectional multicenter study of patients with urea cycle disorders in the United States
Mol. Genet. Metab.
(2008) Neurologic damage and neurocognitive dysfunction in urea cycle disorders
Semin. Pediatr. Neurol.
(2008)Current strategies for the management of neonatal urea cycle disorders
J. Pediatr.
(2001)- et al.
Urea cycle disorders: diagnosis, pathophysiology, and therapy
Adv. Pediatr.
(1996) - et al.
Urea cycle disorders: clinical presentation outside the newborn period
Crit. Care Clin.
(2005) - et al.
New pathways of nitrogen excretion in inborn errors of urea synthesis
Lancet
(1979) - et al.
Long-term correction of urea cycle disorders
J. Pediatr.
(2001) - et al.
An autopsy case of ornithine transcarbamylase deficiency
Brain Dev.
(2002)
Ornithine transcarbamylase deficiency: neuropathologic changes acquired in utero
J. Pediatr.
Carbamyl phosphate synthetase 1 deficiency: a destructive encephalopathy
Pediatr. Neurol.
Magnetic resonance imaging in late-onset ornithine transcarbamylase deficiency
Brain Dev.
Effects of congenital hyperammonemia on the cerebral and hepatic levels of the intermediates of energy metabolism in spf mice
Biochem. Biophys. Res. Commun.
Dendritic alterations in cortical pyramidal cells in the sparse fur mouse
Brain Res.
Contrasting features of urea cycle disorders in human patients and knockout mouse models
Mol. Genet. Metab.
Ornithine deficiency in the arginase double knockout mouse
Mol. Genet. Metab.
A mouse model of argininosuccinic aciduria: biochemical characterization
Mol. Genet. Metab.
Chronic moderate hyperammonemia impairs active and passive avoidance behavior and conditional discrimination learning in rats
Exp. Neurol.
Effects of ammonia on glutamate transporter (GLAST) protein and mRNA in cultured rat cortical astrocytes
Neurochem. Int.
Taurine rescues hippocampal long-term potentiation from ammonia-induced impairment
Neurobiol. Dis.
Hyperammonemia: regulation of argininosuccinate synthetase and argininosuccinate lyase genes in aggregating cell cultures of fetal rat brain
Neurosci. Lett.
Accumulation of large neutral amino acids in the brain of sparse-fur mice at hyperammonemic state
Biochem. Med. Metab. Biol.
Clinical consequences of urea cycle enzyme deficiencies and potential links to arginine and nitric oxide metabolism
J. Nutr.
Arginine-related guanidino compounds and nitric oxide synthase in the brain of ornithine transcarbamylase deficient spf mutant mouse: effect of metabolic arginine deficiency
Neurosci. Lett.
Nitric oxide in hepatic encephalopathy and hyperammonemia
Neurochem. Int.
Ornithine restores ureagenesis capacity and mitigates hyperammonemia in Otcspf-ash mice
J. Nutr.
Extracellular brain glutamate during acute liver failure and during acute hyperammonemia simulating acute liver failure: an experimental study based on in vivo brain dialysis
J. Hepatol.
Acute insult of ammonia leads to calcium-dependent glutamate release from cultured astrocytes, an effect of pH
J. Biol. Chem.
Role of NMDA receptors in acute liver failure and ammonia toxicity: therapeutical implications
Neurochem. Int.
Evidence of excitotoxicity in the brain of the ornithine carbamoyltransferase deficient sparse fur mouse
Brain Res. Dev. Brain Res.
Differential vulnerability of central neurons of the rat to quinolinic acid
Neurosci. Lett.
Characterization of N-methyl-d-aspartate receptors in the hyperammonemic sparse fur mouse
Brain Res.
Mechanisms of ammonia-induced cell death in rat cortical neurons: roles of NMDA receptors and glutathione
Neurochem. Int.
Ammonia-mediated LTP inhibition: effects of NMDA receptor antagonists and l-carnitine
Neurobiol. Dis.
Cognitive outcome in urea cycle disorders
Mol. Genet. Metab.
Major complications of cirrhosis
Neurological implications of urea cycle disorders
J. Inherit. Metab. Dis.
Neurologic outcome in children with inborn errors of urea synthesis. Outcome of urea-cycle enzymopathies
N. Engl. J. Med.
Outcome and survival of 88 patients with urea cycle disorders: a retrospective evaluation
Eur. J. Pediatr.
Mechanisms of hyperammonemia
Clin. Chem. Lab. Med.
Neurodevelopmental outcome of long-term therapy of urea cycle disorders in Japan
J. Inher. Metab. Dis.
Survival after treatment with phenylacetate and benzoate for urea-cycle disorders
N. Engl. J. Med.
Brain edema and hepatic encephalopathy
Semin. Liver Dis.
Mechanisms of ammonia-induced astrocyte swelling
Metab. Brain Dis.
Effects of hyperammonaemia on brain function
J. Inherit. Metab Dis.
Distinctly abnormal brain metabolism in late-onset ornithine transcarbamylase deficiency
Neurology
Late-onset ornithine transcarbamylase deficiency in male patients: prognostic factors and characteristics of plasma amino acid profile
Pediatr. Int.
An integrated approach to the diagnosis and prospective management of partial ornithine transcarbamylase deficiency
Pediatrics
Ammonia toxicity and its prevention in inherited defects of the urea cycle
Diabetes Obes. Metab.
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