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Base editors can correct disease-causing genetic variants. After a neonate had received a diagnosis of severe carbamoyl-phosphate synthetase 1 deficiency, a disease with an estimated 50% mortality in early infancy, we immediately began to develop a customized lipid nanoparticle–delivered base-editing therapy. After regulatory approval had been obtained for the therapy, the patient received two infusions at approximately 7 and 8 months of age. In the 7 weeks after the initial infusion, the patient was able to receive an increased amount of dietary protein and a reduced dose of a nitrogen-scavenger medication to half the starting dose, without unacceptable adverse events and despite viral illnesses. No serious adverse events occurred. Longer follow-up is warranted to assess safety and efficacy. (Funded by the National Institutes of Health and others.) A lipid nanoparticle–delivered base-editing therapy was custom designed for an infant with a urea-cycle disorder. The affected infant was treated at approximately 7 and 8 months of age.

To our knowledge, no randomized study has shown whether zinc replacement therapy is effective for hyperammonemia in liver cirrhosis; therefore, we performed a double-blind, placebo-controlled trial to examine efficacy and safety of the zinc replacement therapy. Patients with liver cirrhosis and hyperammonemia (at or above the institutional reference value) and hypozincemia (≤65 μg/dL) were enrolled in the outpatient units of the participating institutions and were randomly divided to receive placebo (P group) or zinc acetate preparation at a dose of 3 capsules/d for a total zinc content of 150 mg/d (Z group) by the envelope method. Of the 18 enrolled patients, 6 dropped out; thus, the analyses included 12 patients (5 in the P group and 7 in the Z group). Variations in blood concentrations of zinc and ammonia as well as liver function test results were compared. Blood zinc levels significantly increased in the Z group (P = 0.0037; Friedman test) but not the P group. Blood ammonia levels significantly decreased in the Z group (P = 0.0114; Friedman test) but not the P group. The percent change in blood ammonia level also revealed significant reduction at the eighth week in the Z group (P = 0.0188: Mann-Whitney test). No serious adverse events attributable to the zinc preparation were noted. Although this study is preliminary and includes a small sample, it is, to our knowledge, the first randomized controlled trial to show that zinc supplementation for 3 mo seems effective and safe for treating hyperammonemia in liver cirrhosis. Studies with a larger sample size are needed to confirm our findings.

Sarcopenia is a progressive muscle wasting condition often associated with hyperammonemia. However, no approved animal models of sarcopenia with hyperammonemia were reported. This study aimed to provide a surgical modelling of sarcopenia with hyperammonemia. Male Wistar rats were assigned by the method of random numbers ( n  = 6 per group) into experimental group with ligation of portal and pyloric veins or control group with sham surgery. Blood ammonia levels were measured directly after the surgery (20 min), after 1 h to observe acute damage in functioning shunts, and at the final endpoint (30 days). Rats were sacrificed with histological study of the liver, spleen, cerebral cortex, and skeletal muscles. Experimental rats revealed hyperammonemia at 30 days compared to controls, 70 µmol/L versus 38 µmol/L, p <0.05. No significant changes were observed in liver morphology between the groups, approving hyperammonemia without liver damage. Splenomegaly and Gamna-Gandy bodies in the spleen of experimental rats indirectly evidenced functionable portosystemic shunting after the ligation. Cerebral cortex showed a significant decrease in neurons of experimental animals, 7.6 ± 2.5 NeuN + cells vs 13 ± 2 in controls, p <0.05. Skeletal muscles revealed a significant difference of muscle fiber diameter between the groups, 20.2 ± 2.1 µm in the experimental group vs 30.7 ± 4.3 µm in controls, at p < 0.001. A model of sarcopenia with hyperammonemia was established with concomitant changes in cerebral histology revealed. This model may be a valuable tool for studies of sarcopenia and related therapeutic options.

Valproic acid, frequently prescribed for neurological and psychiatric disorders, can cause hyperammonemia (HA). This retrospective study aimed to investigate the association among the basic characteristics, comorbidities, co-medications, and risk of HA in patients receiving valproic acid. We compared groups with and without HA using data collected from the medical records of adults undergoing valproic acid monitoring between January 1, 2019, and December 31, 2021. We conducted a multivariable logistic regression analysis to explore the risk factors for HA and a comprehensive systematic literature review to identify factors significantly associated with valproic acid-related HA. In total, 247 patients were included, with 37 in the HA group (serum ammonia level > 150 mcg/dL); almost all of them eventually developed hyperammonemic encephalopathy (HE). Multivariable logistic regression analysis revealed that valproic acid levels (odds ratio (OR): 1.01, 95% confidence interval (CI): 0.99 - 1.03), epilepsy (OR: 3.82, 95% CI: 1.52 - 9.62), congestive heart failure (OR: 32.3, 95% CI: 4.09 - 255.4), and concomitant phenytoin use (OR: 6.4, 95% CI: 1.07 - 38.12) are independently associated with HA development during valproic acid therapy. Our data and those of previous studies demonstrate significant associations of valproic acid-related HA with concomitant phenytoin and topiramate use; serum valproic acid concentrations were also significantly positively correlated with serum ammonia levels. The results suggest that serum ammonia and valproic acid levels should be monitored during valproic acid treatment, particularly with concurrent use of phenytoin or topiramate, to prevent further deterioration of HE.

Background Although primarily reported in solid organ transplant recipients and patients undergoing chimeric antigen receptor T‐cell immunotherapy (CAR‐T), non‐hepatic hyperammonemia (NHHA) is a rare but lethal complication in the broader context of post‐ chemo‐immunotherapy hematologic malignancies. It often presents with unexplained encephalopathy that mimics primary central nervous system (CNS) progression, leading to diagnostic delays. With the expanding use of bispecific antibodies (e.g., glofitamab), the etiology of NHHA, particularly the complex interplay between opportunistic infections and potential metabolic susceptibility, remains poorly understood. Case Presentation We report a fatal case of NHHA in a 58‐year‐old male with diffuse large B‐cell lymphoma (DLBCL) following glofitamab‐based chemo‐immunotherapy. The patient developed sudden onset altered mental status with extreme hyperammonemia (peak blood ammonia 638.9 µmol/L) despite preserved liver function. Metagenomic next‐generation sequencing (mNGS) of bronchoalveolar lavage fluid identified Ureaplasma urealyticum. Furthermore, post‐mortem whole‐exome sequencing (WES) identified a heterozygous variant of SLC25A13 (NM₀14251.3:c.2 T > C). As biochemical confirmation of citrin deficiency was not available, the clinical significance of this variant remains uncertain, though it may represent a contributory metabolic susceptibility factor. Despite aggressive ammonia‐lowering strategies, including continuous renal replacement therapy (CRRT) and targeted antibiotics, the patient succumbed to fulminant cerebral edema. Conclusion This case highlights the Ureaplasma urealyticum infection as a critical precipitant of fatal NHHA following glofitamab therapy, occurring in the background of possible genetic metabolic susceptibility (an unverified heterozygous SLC25A13 variant of uncertain functional significance). These findings underscore the critical need for early blood ammonia monitoring and rapid mNGS screening in immunocompromised patients with unexplained encephalopathy. We propose a structured diagnostic algorithm to expedite the recognition and management of this reversible yet life‐threatening condition.

Urea cycle disorders (UCDs) are inborn errors of ammonia detoxification/arginine synthesis due to defects affecting the catalysts of the Krebs-Henseleit cycle (five core enzymes, one activating enzyme and one mitochondrial ornithine/citrulline antiporter) with an estimated incidence of 1:8.000. Patients present with hyperammonemia either shortly after birth (~50%) or, later at any age, leading to death or to severe neurological handicap in many survivors. Despite the existence of effective therapy with alternative pathway therapy and liver transplantation, outcomes remain poor. This may be related to underrecognition and delayed diagnosis due to the nonspecific clinical presentation and insufficient awareness of health care professionals because of disease rarity. These guidelines aim at providing a trans-European consensus to: guide practitioners, set standards of care and help awareness campaigns. To achieve these goals, the guidelines were developed using a Delphi methodology, by having professionals on UCDs across seven European countries to gather all the existing evidence, score it according to the SIGN evidence level system and draw a series of statements supported by an associated level of evidence. The guidelines were revised by external specialist consultants, unrelated authorities in the field of UCDs and practicing pediatricians in training. Although the evidence degree did hardly ever exceed level C (evidence from non-analytical studies like case reports and series), it was sufficient to guide practice on both acute and chronic presentations, address diagnosis, management, monitoring, outcomes, and psychosocial and ethical issues. Also, it identified knowledge voids that must be filled by future research. We believe these guidelines will help to: harmonise practice, set common standards and spread good practices with a positive impact on the outcomes of UCD patients.

Background Urea cycle disorders (UCDs) are rare inherited metabolic defects of ammonia detoxification. In about half of patients presenting with a UCD, the first symptoms appear within a few days after birth. These neonatal onset patients generally have a severe defect of urea cycle function and their survival and outcome prognoses are often limited. To understand better the current situation of neonatal onset in UCDs, we have performed a multicentre, retrospective, non-interventional case series study focussing on the most severe UCDs, namely defects of carbamoyl phosphate synthetase 1 (CPS1), ornithine transcarbamylase (OTC), and argininosuccinate synthetase (ASS). Methods and results Data of 63 patients were collected (27 patients with ASS deficiency, 23 patients with OTC deficiency, and 12 patients with CPS1 deficiency, one patient definite diagnosis not documented). The majority of patients (43/63, 68 %) had an initial ammonia concentration exceeding 500 μmol/L (normal < 100), of which most (26/43, 60.5 %) were also encephalopathic and were treated with hemodialysis. In patients surviving the initial crisis, recurrence of hyperammonemic events within the first 1.5 years of life occurred frequently (mean 3.6 events, range 0–20). Of all patients, 16 (25.4 %) died during or immediately after the neonatal period. Conclusion We observed in this cohort of neonatal onset UCD patients a high rate of initial life-threatening hyperammonemia and a high risk of recurrence of severe hyperammonemic crises. These corresponded to a high mortality rate during the entire study period (30.2 %) despite the fact that patients were treated in leading European metabolic centers. This underlines the need to critically re-evaluate the current treatment strategies in these patients.

Arginase deficiency is caused by biallelic mutations in arginase 1 (ARG1), the final step of the urea cycle, and results biochemically in hyperargininemia and the presence of guanidino compounds, while it is clinically notable for developmental delays, spastic diplegia, psychomotor function loss, and (uncommonly) death. There is currently no completely effective medical treatment available. While preclinical strategies have been demonstrated, disadvantages with viral-based episomal-expressing gene therapy vectors include the risk of insertional mutagenesis and limited efficacy due to hepatocellular division. Recent advances in messenger RNA (mRNA) codon optimization, synthesis, and encapsulation within biodegradable liver-targeted lipid nanoparticles (LNPs) have potentially enabled a new generation of safer, albeit temporary, treatments to restore liver metabolic function in patients with urea cycle disorders, including ARG1 deficiency. In this study, we applied such technologies to successfully treat an ARG1-deficient murine model. Mice were administered LNPs encapsulating human codon-optimized ARG1 mRNA every 3 d. Mice demonstrated 100% survival with no signs of hyperammonemia or weight loss to beyond 11 wk, compared with controls that perished by day 22. Plasma ammonia, arginine, and glutamine demonstrated good control without elevation of guanidinoacetic acid, a guanidino compound. Evidence of urea cycle activity restoration was demonstrated by the ability to fully metabolize an ammonium challenge and by achieving near-normal ureagenesis; liver arginase activity achieved 54% of wild type. Biochemical and microscopic data showed no evidence of hepatotoxicity. These results suggest that delivery of ARG1 mRNA by liver-targeted nanoparticles may be a viable gene-based therapeutic for the treatment of arginase deficiency.

Background Hyperammonemia induces neuroinflammation and increases GABAergic tone in the cerebellum which contributes to cognitive and motor impairment in hepatic encephalopathy (HE). The link between neuroinflammation and GABAergic tone remains unknown. New treatments reducing neuroinflammation and GABAergic tone could improve neurological impairment. The aims were, in hyperammonemic rats, to assess whether: Enhancing endogenous anti-inflammatory mechanisms by sulforaphane treatment reduces neuroinflammation and restores learning and motor coordination. Reduction of neuroinflammation by sulforaphane normalizes extracellular GABA and glutamate-NO-cGMP pathway and identify underlying mechanisms. Identify steps by which hyperammonemia-induced microglial activation impairs cognitive and motor function and how sulforaphane restores them. Methods We analyzed in control and hyperammonemic rats, treated or not with sulforaphane, (a) learning in the Y maze; (b) motor coordination in the beam walking; (c) glutamate-NO-cGMP pathway and extracellular GABA by microdialysis; (d) microglial activation, by analyzing by immunohistochemistry or Western blot markers of pro-inflammatory (M1) (IL-1b, Iba-1) and anti-inflammatory (M2) microglia (Iba1, IL-4, IL-10, Arg1, YM-1); and (e) membrane expression of the GABA transporter GAT-3. Results Hyperammonemia induces activation of astrocytes and microglia in the cerebellum as assessed by immunohistochemistry. Hyperammonemia-induced neuroinflammation is associated with increased membrane expression of the GABA transporter GAT-3, mainly in activated astrocytes. This is also associated with increased extracellular GABA in the cerebellum and with motor in-coordination and impaired learning ability in the Y maze. Sulforaphane promotes polarization of microglia from the M1 to the M2 phenotype, reducing IL-1b and increasing IL-4, IL-10, Arg1, and YM-1 in the cerebellum. This is associated with astrocytes deactivation and normalization of GAT-3 membrane expression, extracellular GABA, glutamate-nitric oxide-cGMP pathway, and learning and motor coordination. Conclusions Neuroinflammation increases GABAergic tone in the cerebellum by increasing GAT-3 membrane expression. This impairs motor coordination and learning in the Y maze. Sulforaphane could be a new therapeutic approach to improve cognitive and motor function in hyperammonemia, hepatic encephalopathy, and other pathologies associated with neuroinflammation by promoting microglia differentiation from M1 to M2.

Abstract A 3.5-year-old girl with genetically proven distal renal tubular acidosis presented with lethargy, after numerous episodes of vomiting and poor feeding. Laboratory investigations revealed severe metabolic acidosis, hypokalemia and a serum ammonia level of 515 mmol/L (normal range: 19–50 mmol/L). Despite treatment with sodium bicarbonate, potassium supplementation, sodium benzoate and carglumic acid, her condition required hemodialysis, which resulted in rapid improvement in clinical and metabolic parameters. Hyperammonemia in distal renal tubular acidosis results from impaired ammonium excretion and increased ammoniagenesis due to hypokalemia and chronic metabolic acidosis, particularly during metabolic decompensation. This case had the highest ever reported serum ammonia level in distal renal tubular acidosis with encephalopathic findings, necessitating hemodialysis treatment. Routine monitoring of serum ammonia levels in distal renal tubular acidosis patients during metabolic stress is essential. Graphical Abstract