The most representative of these are organic acidemias, e.g., methylmalonic, propionic, and isovaleric acidemia, wherein the hyperammonemia is a result of the inhibition of NAGS and/or CPS1 by intermediary metabolites (e.g., methylmalonic or propionic acid, isovalerylglycine) accumulating due to the enzymatic defect. Secondary hyperammonemias accompany metabolic disorders, i.e., organic acidurias, where the urea cycle malfunction is a consequence of enzymatic aberrations disabling the synthesis of the urea cycle substrates. The most common UCD is an X-linked deficiency in ornithine transcarbamylase (OTC), whereas autosomally recessive inherited deficiency in N-acetyl glutamate synthase (NAGS), carbamoyl synthase (CPS1), argininosuccinate synthetase (ASS), argininosuccinate lyase (ASL), or arginase 1 (AR1) are less frequent.
Mutations in any of the genes constituting the urea cycle, encoding six enzymes and two mitochondrial transporters, lead to urea cycle disorders (UCDs), termed ‘primary hyperammonemias’. The S100B measure may support the development of therapeutic targets and clinical monitoring in these disorders.
Overall, the linear correlation between ammonia and S100B but not standard oxidative stress-related markers offers a unique perspective for the future identification and monitoring of neurological deficits risk-linked with hyperammonemia episodes in patients with inherited hyperammonemias. S100B was positively correlated with plasma ammonia level, while noticeable levels of circulating 3-NT in some of the patients’ plasma did not correlate with ammonia concentration. Also, the level of pro- and anti-inflammatory mediators (i.e., IL-12, IL-6, IL-8, TNF-α, IL-1β, and IL-10) and chemokines (IP-10, MCP-1, MIG, and RANTES) were quantified. The plasma biomarkers listed above were determined for the first time in congenital hyperammonemia. Further, we analyzed three mechanistically diverged but linked with oxidative–nitrosative stress biochemical parameters: 3-nitrotyrosine (3-NT), a measure of plasma proteins’ nitration advanced oxidation protein products (AOPP), a measure of protein oxidation and glutathione peroxidase (GPx) activity, a measure of anti-oxidative enzymatic capacity. In order to find a new, systemic marker common to the course of congenital hyperammonemias, we decided to measure the plasma level of S100 calcium-binding protein B (S100B), which is associated with cerebral impairment. Individuals with inherited hyperammonemias often present developmental and intellectual deficiencies which are likely to be exaggerated by hyperammonemia episodes in long-term outcomes.
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