2026-01-31 | Impact of glycerol phenylbutyrate on biochemistry and outcomes in paediatric patients with urea cycle disorders: a multicentre case series from Saudi Arabia.
BACKGROUND: Urea cycle disorders (UCDs) are rare inherited conditions that disrupt ammonia detoxification, leading to hyperammonaemia and potential neurological harm. In Saudi Arabia, high consanguinity rates increase UCD birth incidence. Traditional nitrogen scavengers - sodium benzoate (NaBz) and sodium phenylbutyrate (NaPBA) - are limited by poor palatability, high sodium burden, and large dosing volumes. Glycerol phenylbutyrate (GPB) offers improved pharmacological and practical properties, including slow intestinal hydrolysis, reduced dosing frequency, absence of sodium and propylene glycol, and better tolerability. This study assessed real-world outcomes of GPB in a paediatric UCD population. METHODS: We conducted a retrospective analysis of 37 paediatric patients from three Saudi hospitals. Pre- and post-GPB data were compared for plasma ammonia, hyperammonaemic crises (HACs), HAC-related hospitalisations and durations, growth z-scores, and adverse events. A caregiver survey (n = 15) captured treatment experiences and preferences. RESULTS: GPB significantly reduced routine plasma ammonia levels by 21% (median 72 to 57 µmol/L, p = 0.011), with the proportion of patients above the local reference range dropping from 74% to 42%. Annualised HAC rates fell by 55% (2.2 to 1.0/year), HAC-related hospitalisations by 27% (1.1 to 0.8/year), and annualised HAC-related hospital stays by 24% (3.3 to 2.5 days/year), though these did not reach statistical significance. Growth z-scores showed small, non-significant upward trends (+ 0.2 for height and weight). GPB was well tolerated, with no treatment-related adverse events. All survey respondents (15/15) preferred GPB over NaBz and NaPBA. 100% rated GPB equal or superior in controlling ammonia levels and being easier to adhere to, and 85% found it equal or better for palatability. CONCLUSIONS: GPB improved biochemical control and showed consistent trends toward reduced clinical burden in a real-world paediatric UCD cohort. Although some outcomes were not statistically significant, likely due to sample size and inter-individual variability, the magnitude and direction of change - supported by unanimous patient preference - highlight GPB’s advantages. These findings support its use as a first-line or step-up therapy in paediatric UCDs.
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2026-01-05 | Radiation therapy in a ductal carcinoma in situ patient with ornithine transcarbamylase deficiency: a case report.
Ornithine transcarbamylase (OTC) deficiency is a rare urea cycle disorder that impairs ammonia detoxification, increasing the risk of hyperammonemic crises under metabolic stress. While chemotherapy-related risks have been reported, data on the safety of ionizing radiation therapy (RT) in this population are limited. This case describes a 30-year-old woman with late-onset OTC deficiency diagnosed with right-sided ductal carcinoma in situ. She underwent segmental mastectomy followed by adjuvant 3D conformal RT (40 Gy in 15 fractions with a concomitant boost to 48 Gy). Her multidisciplinary care involved preoperative hydration, close nutritional monitoring, and serial ammonia measurements. She completed RT without treatment interruptions or signs of hyperammonemia. This case illustrates that breast RT can be delivered safely in patients with OTC deficiency with a multidisciplinary, preventative approach. To our knowledge, this is the first report describing RT planning and metabolic surveillance in this population.
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2025-11-09 | Hyperuricemia increases susceptibility to chronic kidney injury exacerbation via autophagic flux blockade-mediated ammonia death pathway.
Ammonia (NH3), a core toxic byproduct of amino acid metabolism in the body, poses a severe threat to cell survival when its homeostasis is disrupted. Maintaining low systemic ammonia concentrations is crucial. Under physiological conditions, the kidneys regulate ammonia metabolism precisely through glutaminase 1 (GLS1)-mediated ammonia production and the urea cycle, ensuring efficient detoxification. Hyperuricemic nephropathy (HN), a common complication of hyperuricemia, impairs patient health significantly. However, whether and how ammonia toxicity triggers cell death under this pathological condition remains unclear. Here, we demonstrated that HN promoted ammonia-dependent cell death by blocking autophagic flux, revealing a novel mechanism of HN injury. In vivo and in vitro models were used to evaluate the lysosome mitochondria damage and autophagic flux arrest mechanism caused by ammonia metabolism disorder through ultrastructural analysis, fluorescent probe and autophagic flux detection, and the causal association was verified by ammonia scavengers and gene intervention. Mechanistically, chronic hyperuricemic stress accelerates renal glutaminolysis to mitigate injury and generate sufficient ATP, resulting in excessive mitochondrial ammonia production. The ammonia accumulated undergoes RHCG-dependent transmembrane transport, causing lysosomal alkalinization and dysfunction, further resulting in mitochondrial ammonia retention and swelling. This ultimately inhibited autolysosomal disassembly, which impaired the clearance of damaged mitochondria and constitutes autophagic flux blockade, consequently driving cell death. These findings identified a distinct form of cell death in HN, mechanistically divergent from previously known mechanisms such as apoptosis or pyroptosis. It redefined HN pathogenesis through a metabolic lens, identifying druggable targets to mitigate renal damage in hyperuricemic patients.
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2025-10-30 | Nitrogen Scavengers: History, Clinical Considerations and Future Prospects.
Nitrogen scavengers play a critical role in treating acute and chronic hyperammonemia, especially in urea cycle disorders (UCDs), where impaired ammonia detoxification leads to toxic nitrogen accumulation. These agents complement low-protein diets and urea cycle intermediates. Sodium benzoate and sodium phenylacetate are the main scavengers, conjugating with glycine and glutamine to form hippurate and phenylacetylglutamine, which are excreted in urine. This therapeutic approach, introduced in the 1980s, was based on early findings linking benzoate to reduced urea excretion. Nitrogen scavengers are also used in secondary hyperammonemia from organic acidemias and fatty acid oxidation disorders, though they may become increasingly ineffective in progressing liver failure due to their reliance on hepatocyte function. To improve tolerability, phenylbutyrate was developed as an oral alternative to phenylacetate and is available in sodium-bound and prodrug forms, but issues with taste and side effects persist. While effective, current treatments target nitrogenous waste products rather than ammonia directly, offering an avenue of future drug development for UCDs. This review discusses the chemical properties, clinical use, and limitations of nitrogen scavengers, hereby focusing on phenylacetate and related substances, and highlights the need for improved therapies, including approaches that directly target ammonia removal. For the benefit of readers already experienced in nitrogen scavengers for UCDs, we also include considerations concerning the use of these drugs in animal experiments and a viewpoint on ornithine phenylacetate as a related substance.
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