Objectives

To discuss the urea cycle To be able to enumerate and explain the inborn errors of urea synthesis To describe the similarities and differences in manifestations and lab findings between the different inborn errors of the urea synthesis To discuss the benzoate/phenylacetate as treatment for urea cycle defects

HYPERGLUTAMINEMIA
Manifests as a psychological problem due to build up of glutamate and ammonia Glutamine: Proliferates in the CNS Interstitial and CSF concentrations: one order magnitude higher than any other amino acids Transport from blood to brain is insufficient to meet the demand of the brain tissues for this amino acid

 A major proportion of astroglia-derived Glutamine is shuttled to neurons where it is degraded by phosphate-activated glutaminase giving rise to the excitatory neurotransmitter amino acid glutamate. Glutamate released from neurons is taken up by astrocytes,and reconverted to glutamine. Glutamine effluxes from astrocytes, its neuronal uptake and enters to the blood via the cerebral capillary endothelial cells are mediated by different amino acid carriers. The glutamine, specific carriers also largely contribute to glutamine efflux from the brain to the vascular bed Excessive accumulation of glutamine in brain cells may be deleterious to brain function. The brain relies on glutamine synthesis for the removal of excess ammonia and the temporary storage of nitrogen.

 As this process is predominantly localized in the astrocytes, acute hyperammonemia causes increased intracellular production of glutamine from glutamate and ammonia via glutaminesynthetase, which leads to astrocyte swelling and dysfunction. Excess Gln is released into the extracellular space, and directly alters the local astrocyte-neuronal synaptic environment. A consequent imbalance of excitatory versus inhibitory neurotransmission occurs because of increased glutamate production in conjunction with decreased synaptic uptake of glutamate .In hyperammonemia, excess glutamine leads to cerebral edema, which largely results from its interference with mitochondrial function

Altered level of consciousness ( lethargy, coma, including mental disorder, irritability, low IQ) Evident when there is already hyperammonemia It would lead to accumulation of ammonia and glutamine in the brain will increase the level of glutamine ( excessive accumulation of Gln in brain cells may be deleterious to the brain function