Abstract
ABSTRACTThe urea cycle functions to incorporate ammonia, generated by normal metabolism, into urea. Urea cycle disorders (UCDs) are caused by loss of function in any of the enzymes responsible for ureagenesis, and are characterized by life-threatening episodes of acute metabolic decompensation with hyperammonemia (HA). A prospective analysis of interim HA events in a cohort of individuals with ornithine transcarbamylase (OTC) deficiency, the most common UCD, revealed that intercurrent infection was the most common precipitant of acute HA and was associated with markers of increased morbidity when compared with other precipitants. To further understand these clinical observations, we developed a model system of metabolic decompensation with HA triggered by viral infection (PR8 influenza) using spf-ash mice, a model of OTC deficiency. Both wild-type (WT) and spf-ash mice displayed similar cytokine profiles and lung viral titers in response to PR8 influenza infection. During infection, spf-ash mice displayed an increase in liver transaminases, suggesting a hepatic sensitivity to the inflammatory response and an altered hepatic immune response. Despite having no visible pathological changes by histology, WT and spf-ash mice had reduced CPS1 and OTC enzyme activities, and, unlike WT, spf-ash mice failed to increase ureagenesis. Depression of urea cycle function was seen in liver amino acid analysis, with reductions seen in aspartate, ornithine and arginine during infection. In conclusion, we developed a model system of acute metabolic decompensation due to infection in a mouse model of a UCD. In addition, we have identified metabolic perturbations during infection in the spf-ash mice, including a reduction of urea cycle intermediates. This model of acute metabolic decompensation with HA due to infection in UCD serves as a platform for exploring biochemical perturbations and the efficacy of treatments, and could be adapted to explore acute decompensation in other types of inborn errors of metabolism.
Highlights
The urea cycle (UC; supplementary material Fig. S1) is present only in the liver and serves two purposes: (1) the de novo biosynthesis and degradation of arginine, and (2) the incorporation of excess nitrogen into urea
In a prospective analysis of a cohort of patients with ornithine transcarbamylase deficiency (OTCD), the most common Urea cycle disorders (UCDs), the authors identified infection as the most common identifiable cause of acute decompensation with HA, and this was associated with markers of increased morbidity
To further understand these clinical observations, the authors developed a model system of metabolic decompensation with HA triggered by viral infection [influenza A/Puerto Rico/8/34 (PR8) virus] using spf-ash mice, an animal model of OTCD
Summary
The urea cycle (UC; supplementary material Fig. S1) is present only in the liver and serves two purposes: (1) the de novo biosynthesis and degradation of arginine, and (2) the incorporation of excess nitrogen into urea. UC disorders (UCDs) are caused by loss of function in any of the enzymes responsible for ureagenesis, and are characterized by life-threatening episodes of acute metabolic decompensation with hyperammonemia (HA). The incidence of these disorders has been estimated at 1 in 30,000 live births (Summar and Tuchman, 2001). In proximal (mitochondrial) UCD [N-acetylglutamate synthetase (NAGS), carbamoyl phosphate synthetase 1 (CPS1) and ornithine transcarbamylase (OTC) deficiencies], ammonia disposal is severely compromised. In distal (cytosolic) UCD [arginosuccinate synthetase (ASS), arginosuccinate lyase (ASL) and arginase (ARG1) deficiencies], ammonia disposal is not as severely impaired and characteristic amino acid metabolites accumulate
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