DeCure for Hyperammonemia due to N-acetylglutamate synthase deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hyperammonemia due to N-acetylglutamate synthase deficiency — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleHyperammonemia due to N-acetylglutamate synthase deficiency maps to a 1-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for hyperammonemia due to n-acetylglutamate synthase deficiency is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
What the evidence adds up to
A 1994 case report describes a neonate with NAGS deficiency who presented with hyperammonaemic coma. At 25 days of life, a test with carbamylglutamate was performed, and the child was then treated with carbamylglutamate three or four times daily at a total dose of 80–100 mg/kg per day. By one year of age, the boy was receiving 200 mg four times a day and had normal somatic and neurological development with good metabolic balance. A 2020 systematic literature review identified 98 cases of NAGS deficiency from 79 families across 48 articles. Of these, 57 were neonatal cases, 34 were post-neonatal, one was diagnosed prenatally, and six did not specify age at presentation or were asymptomatic. Management usually consisted of carbamylglutamate, though maintenance doses varied across reports; protein restriction, citrulline, arginine, and sodium benzoate were also used.
A 2014 case report describes a patient with chemotherapy-induced hyperammonemic encephalopathy who had no underlying urea cycle disorder. A trial of carglumic acid, a synthetic analogue of the product of NAGS, was successful in treating the hyperammonemia. The authors suggest that, in some cases, hyperammonemia may be secondary to chemotherapy and can be treated by overcoming proximal inhibition of the urea cycle. A 2025 French bi-centric retrospective study of 184 adults with hyperammonemia (median peak ammonia 155 μmol/L) found that 61 patients (33%) presented with coma. Non-genetic liver failure or portosystemic shunt was present in 133 patients. Thirteen patients had a genetically confirmed inherited metabolic disease diagnosed in adulthood. In a second cohort of 17 patients, genetic testing was positive in 5 of 6 patients with suggestive biochemical profiles, but negative in patients without such profiles. The authors concluded that in acute episodes with an acquired cause of hyperammonemia, genetic investigations had a low yield.
A 2017 study of five cases of hyperammonemia due to ornithine carbamyltransferase deficiency (a different urea cycle disorder) found heterogeneous mutations and abnormal enzyme kinetics; this abstract does not concern NAGS deficiency or carbamylglutamate treatment. The 2020 review notes that DNA testing is the preferred method for diagnosing NAGS deficiency, though a therapeutic trial of carbamylglutamate may also be helpful. The review calls for further research on the roles of protein restriction and supplements, especially during illness or when carbamylglutamate is unavailable. What remains missing are prospective data on optimal dosing of carbamylglutamate, clear evidence on the benefit of protein restriction and supplementary amino acids, and a standardised diagnostic pathway for adults presenting with hyperammonemia without an obvious acquired cause.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Inherited Metabolic Disease · 1994 · 58 citations
A new neonatal case of<i>N</i>‐acetylglutamate synthase deficiency treated by carbamylglutamate
AbstractN-Acetylglutamate synthase (NAGS) deficiency is a rare, autosomal recessive urea-cycle disease. Its clinical presentation is not different from the other hereditary hyperammonaemias. We report a new neonatal case with hyperammonaemic coma. A test by carbamylglutamate was performed at 25 days of life. Since then, the child was treated by carbamylglutamate three or four times a day with a total dose of 80-100 mg/kg per day. Today, the boy is 1 year old. He receives carbamylglutamate 200 mg four times a day. He has normal somatic and neurological development and good metabolic balance.
Heterogenous Mutations of the Structural Geneof Human Ornithine Carbamyltransferaseas Observed in Five Personal Cases
AbstractA kinetic study dealing with an enzyme deficiency was undertaken in five cases of hyperammonemia secondary to ornithine carbamyltransferase deficiency, and including the parents in three cases. The K(m) for the two substrates were determined in all cases. In three of them, there was an abnormal affinity for one of the substrates. In the two others, the affinities were normal, but different abnormal biochemical behaviors were noted. The examination of the parents revealed that the transmission of the trait was through the mothers.
Current Oncology · 2014 · 15 citations · open access
Hyperammonemic Encephalopathy in An Adenocarcinoma Patient Managed with Carglumic Acid
AbstractHyperammonemic encephalopathy (he) is a rare complication of malignancy and chemotherapy. Although the cause of he is unclear, a functional arginine deficiency secondary to increased catabolism has been suggested as a possible mechanism. Either that deficiency or an undetermined metabolite could lead to inhibition of N-acetylglutamate synthase (nags), a urea cycle enzyme, resulting in hyperammonemia. We present a case of chemotherapy-induced he in a patient with no underlying primary urea cycle disorder. The patient had a successful trial of carglumic acid (a synthetic analog of the product of nags), which suggests that, at least in some cases, he can be treated by overcoming proximal inhibition of the urea cycle. Further, our case is the first in the literature to exclude genetic defects and disorders of the proximal urea cycle, suggesting that hyperammonemia in these patients is probably secondary to chemotherapy.
Molecular Genetics and Metabolism · 2025 · 0 citations · open access
Clinical, biochemical, and molecular findings in adults with hyperammonemia: A French bi-centric retrospective study
AbstractINTRODUCTION: Regardless of its mechanism, hyperammonemia can cause coma and death, and requires urgent management. This study aims at describing the landscape of causes of hyperammonemia in adults and at evaluating the performance of targeted next-generation sequencing (NGS) in this setting. METHODS: We analyzed two cohorts. The first included patients aged ≥15 years presenting with hyperammonemia ≥100 μmol/L at Necker-Enfants Malades (NEM) University Hospital for 10 years and at Toulouse University Hospital for 1.5 years. The second cohort included patients who underwent genetic testing for inherited metabolic disease (IMD) via targeted NGS at NEM hospital over a 5 year-period, regardless of their inclusion in the first cohort, all with hyperammonemia ≥100 μmol/L after age 15. RESULTS: We included 184 patients in the first cohort, with a median peak ammonia concentration of 155 μmol/L. Among them, 61 patients (33 %) presented with coma. Non-genetic liver failure or portosystemic shunt was present in 133 patients. Twenty-three patients had received asparaginase treatment (none with coma despite a median ammonia level of 257 μmol/L), 7 had received valproic acid, 3 had undergone surgical ureterorectal anastomosis, 2 had multiple myeloma, 1 was receiving 5-Fluorouracil (5FU) for metastatic gastrointestinal cancer, 1 had disseminated atypical mycobacteriosis with Mycobacterium genavense (urease-producing bacteria) in a renal transplant setting and 13 had a genetically confirmed IMD diagnosed in adulthood. In the second cohort of 17 patients, genetic testing was positive in 5 of 6 patients with IMD-suggestive biochemical profiles (2 CPS1 deficiencies, 1 OTC deficiency, 1 multiple acyl-coA dehydrogenase deficiency, and 1 lysinuric protein intolerance), and negative in patients without biochemical profile suggesting an IMD. Among them, four patients suffered from protein malnutrition related to various severe conditions (gastric bypass, metastatic colorectal adenocarcinoma, Duchenne muscular dystrophy, and short bowel syndrome). CONCLUSION: The causes of hyperammonemia in adults are varied. In cases of acute episodes without unequivocal metabolic profiles (when unwell) and with an acquired identified cause of hyperammonemia, genetic investigations had a low yield.
Presentation and management of N-acetylglutamate synthase deficiency: a review of the literature
AbstractAbstract Background N-Acetylglutamate synthase (NAGS) deficiency is an extremely rare autosomal recessive metabolic disorder affecting the urea cycle, leading to episodes of hyperammonemia which can cause significant morbidity and mortality. Since its recognition in 1981, NAGS deficiency has been treated with carbamylglutamate with or without other measures (nutritional, ammonia scavengers, dialytic, etc.). We conducted a systematic literature review of NAGS deficiency to summarize current knowledge around presentation and management. Methods Case reports and case series were identified using the Medline database, as well as references from other articles and a general internet search. Clinical data related to presentation and management were abstracted by two reviewers. Results In total, 98 cases of NAGS deficiency from 79 families, in 48 articles or abstracts were identified. Of these, 1 was diagnosed prenatally, 57 were neonatal cases, 34 were post-neonatal, and 6 did not specify age at presentation or were asymptomatic at diagnosis. Twenty-one cases had relevant family history. We summarize triggers of hyperammonemic episodes, diagnosis, clinical signs and symptoms, and management strategies. DNA testing is the preferred method of diagnosis, although therapeutic trials to assess response of ammonia levels to carbamylglutamate may also be helpful. Management usually consists of treatment with carbamylglutamate, although the reported maintenance dose varied across case reports. Protein restriction was sometimes used in conjunction with carbamylglutamate. Supplementation with citrulline, arginine, and sodium benzoate also were reported. Conclusions Presentation of NAGS deficiency varies by age and symptoms. In addition, both diagnosis and management have evolved over time and vary across clinics. Prompt recognition and appropriate treatment of NAGS deficiency with carbamylglutamate may improve outcomes of affected individuals. Further research is needed to assess the roles of protein restriction and supplements in the treatment of NAGS deficiency, especially during times of illness or lack of access to carbamylglutamate.
Presentation and management of N-acetylglutamate synthase deficiency: a review of the literature
AbstractAbstract Background N-Acetylglutamate synthase (NAGS) deficiency is an extremely rare autosomal recessive metabolic disorder affecting the urea cycle, leading to episodes of hyperammonemia which can cause significant morbidity and mortality. Since its recognition in 1981, NAGS deficiency has been treated with carbamylglutamate with or without other measures (nutritional, ammonia scavengers, dialytic, etc.). We conducted a systematic literature review of NAGS deficiency to summarize current knowledge around presentation and management. Methods Case reports and case series were identified using the Medline database, as well as references from other articles and a general internet search. Clinical data related to presentation and management were abstracted by two reviewers. Results In total, 98 cases of NAGS deficiency from 79 families, in 48 articles or abstracts were identified. Of these, 1 was diagnosed prenatally, 57 were neonatal cases, 34 were post-neonatal, and 6 did not specify age at presentation or were asymptomatic at diagnosis. Twenty-one cases had relevant family history. We summarize triggers of hyperammonemic episodes, diagnosis, clinical signs and symptoms, and management strategies. DNA testing is the preferred method of diagnosis, although therapeutic trials to assess response of ammonia levels to carbamylglutamate may also be helpful. Management usually consists of treatment with carbamylglutamate, although the reported maintenance dose varied across case reports. Protein restriction was sometimes used in conjunction with carbamylglutamate. Supplementation with citrulline, arginine, and sodium benzoate also were reported. Conclusions Presentation of NAGS deficiency varies by age and symptoms. In addition, both diagnosis and management have evolved over time and vary across clinics. Prompt recognition and appropriate treatment of NAGS deficiency with carbamylglutamate may improve outcomes of affected individuals. Further research is needed to assess the roles of protein restriction and supplements in the treatment of NAGS deficiency, especially during times of illness or lack of access to carbamylglutamate.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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