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.

Urea cycle disorders (UCDs) are rare inherited metabolic diseases characterized by defective detoxification of nitrogen, leading to hyperammonemia and neurological complications. While pediatric UCDs have been extensively studied in Japan, data on adult patients remain limited. This study aims to evaluate the current status of Japanese adult UCD patients, hereby comparing long-term outcomes after neonatal/infantile or late onset in a new nationwide study investigating clinical manifestations and management. In total, we collected data of 116 adult UCD patients diagnosed and/or treated at various institutions, combining this new cohort (34 UCD patients between January 2010 and December 2022) with data from a previous nationwide study (82 UCD patients between January 2000 and March 2018). Among 116 adult UCD patients, ornithine transcarbamylase deficiency was the most common subtype (N = 69). Hyperammonemia occurred in 91.4% of patients, and intellectual disability was present in 50.0%. Patients generally showed reduced final height and BMI compared to Japanese controls, particularly among females and those with infantile-onset UCDs. Peak ammonia levels ≥ 360 μmol/L were significantly associated with intellectual disability. Liver transplantation (LT) was performed in 20 patients, and although it helped to avoid hyperammonemia, it did not statistically improve neurocognitive outcomes in patients with peak ammonia < 360 μmol/L. This study provides the first comprehensive overview of adult UCD patients in Japan, highlighting frequent growth impairment and variable cognitive outcomes. LT improves metabolic control but cannot prevent intellectual disability in all patients. These findings underscore the need for early diagnosis, individualized treatment strategies, and long-term follow-up into adulthood.

Ammonia can easily cross the blood-brain barrier in its non-ionized form, leading to significant accumulation in the brain during severe hyperammonemia. Excess ammonia is highly toxic to the brain and can cause neurological dysfunctions, such as tremors, ataxia, seizures, coma, and even death. Hyperammonemia is often the primary manifestation of urea cycle disorders (UCDs), a group of inherited metabolic disorders characterized by impaired nitrogen detoxification due to dysfunctions in urea cycle-related enzymes and transporters. Patients with complete deficiencies of urea cycle enzymes typically present with lethargy, hypothermia, anorexia, seizures, abnormal respiratory patterns (hyperventilation or hypoventilation), neurologic posturing, and coma, along with hyperammonemia within a few days after birth. This condition, classified as the neonatal-onset type, frequently results in severe hyperammonemic encephalopathy (≥600 μg/dL [360 μmol/L]) at onset. Hyperammonemia with blood ammonia levels of 600 μg/dL (360 μmol/L) or higher causes significant brain damage. Therefore, at this threshold, hemodialysis is indicated to rapidly remove ammonia and mitigate its harmful effects on the brain. However, even when neonatal-onset UCD patients undergo a combination of hemodialysis and liver transplantation at the onset of severe hyperammonemia (≥600 μg/dL [360 μmol/L]), the neuroprotective effects remain limited. This review aims to describe the pathophysiology of hyperammonemia and UCDs, the impact of hyperammonemia on the brain in UCDs, the role of current therapeutic strategies, and the challenges associated with future treatments for UCDs.

Urea cycle disorders (UCDs) are inherited diseases causing recurrent life-threatening metabolic decompensations due to impaired hepatic ammonia detoxification and decreased ureagenesis. Ornithine transcarbamylase (OTC) deficiency (OTCD) is X-linked and the most common and often fatal UCD. In male hemizygous patients, disease severity primarily depends on the pathogenic sequence variant, while in heterozygous females, disease severity also depends on the X-chromosomal inactivation (XCI) pattern. Females with unfavorable XCI predominantly expressing the mutant OTC protein may be severely affected. Here, we investigated a novel treatment strategy for OTCD since there is an unmet need for better therapies. In the first step, we performed a high throughput screening (HTS) using a diversity library with 10 000 chemical compounds to identify pharmacological chaperone (PC) candidates that stabilize purified wild-type OTC. Stratification of our HTS results revealed five potential PCs, which were selected for further experimentation in cellular systems using primary human hepatocytes (PHHs) and human induced pluripotent stem cell (hiPSC)-derived hepatocytes (hiPSC-Heps) from healthy controls and OTCD patients. Two PCs-PC1 and PC4-increased OTC protein stability and activity in control hiPSC-Heps, while PC4 in addition increased OTC activity in patient-derived PHHs from a female OTCD patient with unfavorable XCI. Finally, PC1 and PC4 both significantly increased ureagenesis in patient-derived PHHs. To conclude, we identified two PCs that stabilized wild-type OTC and enhanced enzyme activity and ureagenesis. Our work suggests that PCs could provide a novel treatment strategy for OTCD specifically in females with unfavorable XCI.

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.