Disease relevance of Hyperammonemia

• Hyperinsulinism and hyperammonemia in infants with regulatory mutations of the glutamate dehydrogenase gene [1].
• Since Reye's syndrome is associated with hyperammonemia, we measured the urea-cycle enzymes in hepatic tissue of 13 patients [2].
• Letter: Nonketotic hyperglycinemia with increased propionic acid excretion and hyperammonemia [3].
• Near-adult cats, fasted overnight, and given a single meal of a complete amino acid diet without arginine, developed hyperammonemia and showed clinical symptoms of ammonia toxicity within 2 hours [4].
• The proband showed severe fasting-induced hypoketotic hypoglycemia, high plasma creatine kinase, heartbeat disorder, hypothermia, and hyperammonemia [5].

Psychiatry related information on Hyperammonemia

• We present the case of a postictal patient with lethargy, hyperammonemia, otherwise normal liver function tests, and a therapeutic valproic acid level [6].
• OTC deficiency is an X-linked disorder that causes hyperammonemia leading to brain damage, mental retardation and death [7].
• In rats with hyperammonemia NMDA had no influence on locomotor activity but it significantly increased memory in a passive avoidance responses [8].
• The authors report the case of a patient who developed hyperammonemia and coma during therapy with valproic acid for affective disorder [9].

High impact information on Hyperammonemia

• We hypothesized that this syndrome of hyperinsulinism and hyperammonemia was caused by excessive activity of glutamate dehydrogenase, which oxidizes glutamate to alpha-ketoglutarate and which is a potential regulator of insulin secretion in pancreatic beta cells and of ureagenesis in the liver [1].
• Treatment of episodic hyperammonemia in children with inborn errors of urea synthesis [10].
• Twelve episodes of hyperammonemia in seven children deficient in carbamyl phosphate synthetase, ornithine transcarbamylase, or argininosuccinic acid synthetase were treated; one patient died and the others recovered [10].
• To treat such episodes, we designed a therapeutic protocol that included prompt recognition of hyperammonemia, therapy with intravenous sodium benzoate, sodium phenylacetate, and arginine, and nitrogen-free intravenous alimentation [10].
• Although normal plasma ammonium levels can be maintained in children with inborn errors of ureagenesis, these children are vulnerable to episodic hyperammonemia often resulting in coma and death [10].

Chemical compound and disease context of Hyperammonemia

• Ornithine transcarbamylase deficiency. Unsuccessful therapy of neonatal hyperammonemia with N-carbamyl-L-glutamate and L-arginine [11].
• Congenital carbamyl phosphate synthetase deficiency was diagnosed by liver biopsy in a 13-year-old girl, alpha-Keto analogues of essential amino acids have been shown to spare nitrogen by reducing urea formation; hence, they were given to this patient in the hope of reducing hyperammonemia and improving protein tolerance [12].
• Protective effect of tert-butanol on hyperammonemia [13].
• Since ornithine also prevented hyperammonemia, it appears that the domestic cat cannot synthesize ornithine [4].
• Renal ammonia and glutamine metabolism during liver insufficiency-induced hyperammonemia in the rat [14].

Biological context of Hyperammonemia

• We recently documented that hyperglucagonemia that occurs as a result of hepatic glycogen depletion may be responsible for this hyperammonemia by promoting gluconeogenesis to provide glucose as a fuel for functioning of several organ systems [15].
• Novel intragenic deletions and point mutations of the ornithine transcarbamylase gene in congenital hyperammonemia [16].
• Valproate-induced hyperammonemia is probably the result of depletion of mitochondrial acetyl CoA and decreased production of N-acetylglutamate, the obligatory activator of the first enzyme of the urea cycle, carbamyl phosphate synthetase I. Anticonvulsant-mediated microsomal enzyme induction may also contribute [17].
• Heterozygote ornithine transcarbamylase deficiency presenting as symptomatic hyperammonemia during initiation of valproate therapy [18].
• It has been shown that chronic hyperammonemia impairs signal transduction pathways associated with NMDA receptors and also alters phosphorylation of some neuronal proteins [19].

Anatomical context of Hyperammonemia

• A decreased level of N-acetylglutamate in liver mitochondria that would follow inhibition of N-acetylglutamate synthetase by propionyl-CoA would be expected to lead to hyperammonemia [20].
• However, chronic hyperammonemia causes pathological changes in perineuronal astrocytes, which may lead to a reduced uptake of released glutamate and a decreased detoxification of ammonia by the brain [21].
• Liver ultrastructure in the four patients with inherited deficiencies of urea cycle enzymes showed minimal alterations with essentially normal mitochondria when biopsy was performed during periods of good control of their hyperammonemia [22].
• In contrast, hyperammonemia was associated with an increase in the affinity and no decrease in the number of glutamate receptors on SM from the hippocampus [23].
• These results demonstrate that during chronic liver insufficiency-induced hyperammonemia, the rat cerebral cortex enhances net ammonia uptake and glutamine release [24].

Gene context of Hyperammonemia

• Mutations of GDH result in hyperinsulinism/hyperammonemia syndrome [25].
• Therefore, it has been proposed that rhesus type B glycoprotein (Rhbg), a member of the Mep/Amt/Rh NH(3) channel superfamily, may be involved in some forms of distal tubular acidosis and congenital hyperammonemia [26].
• We discuss the possibility of a pathogenic role for CNTF and a protective role for beta-synuclein in experimental hyperammonemia [27].
• Activities of monoamine oxidases, MAOA and MAOB, were measured using radiometric assays in different brain regions of the sparse-fur (spf/Y) mouse, a model of congenital hyperammonemia resulting from an X-chromosomal defect of ornithine transcarbamylase [28].
• Seven novel mutations in the ORNT1 gene (SLC25A15) in patients with hyperornithinemia, hyperammonemia, and homocitrullinuria syndrome [29].

Analytical, diagnostic and therapeutic context of Hyperammonemia

• Partial ornithine transcarbamylase deficiency must always be considered in adult women and men with hyperammonemia who have normal liver function test results [30].
• The measured rate of glutamine synthesis under hyperammonemia was 0.43 +/- 0.14 micromol/min per g (mean +/- SD, n = 6), which was significantly higher (unpaired t test; P < 0.01) than that measured in the control group (0.21 +/- 0.04 micromol/ min per g, n = 5) [31].
• Oral administration of sildenafil restores learning ability in rats with hyperammonemia and with portacaval shunts [32].
• Moreover, sildenafil restored the ability of rats with hyperammonemia or with portacaval shunts to learn a conditional discrimination task [32].
• We sought to identify an animal model that would replicate the increases in quinolinate that have been associated with hyperammonemia in humans [33].

References