UCD have yielded insights into disease pathophysiology, the influence of genetic background and the evaluation of novel therapeutics. Two animal models of OTCD, the sparse-fur and the sparse-fur abnormal skin and hair, have been used to study disease pathogenesis and to evaluate therapies. The biochemical characteristics of both of these models include OTCD, elevated plasma ammonia and glutamine, low plasma citrulline and arginine, and elevated urinary orotic acid excretion. In contrast to these previously described models, the spf-J displays a milder phenotype: normal ammonia and plasma orotate at baseline, a small elevation in plasma glutamine, and mild depressions of plasma ornithine, citrulline and arginine. The elevated plasma glutamine seen in spf-J at baseline suggests that ammonia disposal is indeed compromised and that glutamine synthetase may provide an alternative route of elimination. Consistent with this assertion is the depletion of plasma branched chain amino acids, which may be consumed to support glutamine synthesis. Patients with urea cycle disorders experience episodes of acute metabolic decompensation characterized by hyperammonemia. Viral infection is the most common cause of acute metabolic decompensation and is associated with markers of increased morbidity. These findings, combined with the elevation of cerebral amino acids at baseline, supports the hypothesis of altered cerebral amino acid metabolism or transport in spf-j. In the brain, amino acids and their derivatives play a role in synaptic transmission by serving as a source of energy, precursors to neuro-active compounds, allosteric regulators, and even neurotransmitters. Several amino acids involved in various aspects of neurotransmission failed to increase or were depressed in spf-j including glycine, histidine and arginine. These perturbations in the cerebral amino acid pool may be due to decreased transport across the blood brain barrier, depressed synthesis, or increased metabolism. Being that many amino acids are precursors or cofactors for neurotransmission, one could postulate that these perturbations in cerebral amino acids may lead to neurocognitive deficits. Indeed, alterations in cognitive functioning seen in asymptomatic OTC carriers suggest that other factors besides hyperammonemia may play a role. This BAY 73-4506 avenue of inquiry should be explored and necessitates defining the neurocognitive phenotype of spf-j and the relationship between systemic inflammation and brain amino acid metabolism. In conclusion, the spf–J has the benefits of a pure inbred strain, allowing for the ideal characterization of this mild OTC mutation on a uniform genetic background. Added benefits include fecundity and long-term survival. Due to the robust nature of these animals, this model is ideal for studying interactions with other metabolic pathways and mapping of genes that modulate disease activity. Regarding therapeutic approaches, the instability of the enzyme suggests that this model may serve as a target for the preclinical evaluation of small molecule chaperones or activators.