RARE DISEASE
Hyperammonemia due to N-acetylglutamate synthase deficiency
Hyperammonemia due to N-acetylglutamate synthase deficiency
Hyperammonemia due to N-acetylglutamate synthase deficiency
Synonyms: NAGS deficiency
Synonyms: NAGS deficiency
Synonyms: NAGS deficiency
Drug discovery
5
drugs
With orphan designations
Overview
Hyperammonemia due to N-acetylglutamate synthase (NAGS) deficiency is a rare autosomal recessive urea cycle disorder caused by mutations in the NAGS gene, impairing ammonia detoxification. This results in hyperammonemia, presenting as neonatal-onset vomiting, lethargy, seizures, or adult-onset neurological/psychiatric symptoms. Diagnosis relies on elevated ammonia/glutamine, low citrulline, absent urinary orotic acid, and genetic confirmation. Early treatment with N-carbamylglutamate (carglumic acid), a synthetic NAG analog, often normalizes ureagenesis and prevents complications without dietary restrictions. Untreated cases risk irreversible neurological damage or death [1][2][6][7][12].
Therapies
Categories: rare genetic diseases, rare inborn errors of metabolism, rare neurological diseases
Research Papers
65 drug discovery papers about Hyperammonemia due to N-acetylglutamate synthase deficiency, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
65 drug discovery papers about Hyperammonemia due to N-acetylglutamate synthase deficiency, with 3 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-01-01 | P047: Incidental identification of citrullinemia type 1 through carrier screening post liver transplant
Outcome and Follow-Up: Following the addition of carglumic acid, we were able to gradually wean our patient off all additional urea cycle disorder (UCD) management -ammonia scavengers and medical formula -over the course of five months.The patient has not experienced any further hyperammonemic episodes.Citrulline supplementation was discontinued at 11 months and plasma citrulline levels have remained normal to date.Glutamine and alanine levels have remained in normal range, with a maximum glutamine level of 671mol/L.At 21 months of age, the patient remains metabolically stable on carglumic acid 53.6mg/kg/day with dietary protein allotment not exceeding 2.2g/kg/day from intact protein without UCD formula.Developmentally he demonstrates mild-to-moderate delays; likely reflecting his hyperammonemia at presentation.Discussion: This case highlights the importance of early recognition and prompt initiation of carglumic acid in this diagnosis.The identified NAGS c.1289T>C variant adds to the catalog of pathogenic variants identified in this gene.Carglumic acid, an analog of N-acetylglutamate, has proven an effective sole treatment for this enzyme deficiency in our patient with sustained metabolic control.Conclusion: Early diagnosis and prompt initiation of carglumic acid therapy are lifesaving and life-altering in NAGS deficiency.This case contributes to the very limited clinical literature about this diagnosis and its long-term management, while adding to the clinical experience a novel variant.
2024-01-10 | Real-World Experience of Carglumic Acid for Methylmalonic and Propionic Acidurias: An Interim Analysis of the Multicentre Observational PROTECT Study
Methylmalonic aciduria (MMA) and propionic aciduria (PA) are organic acidurias characterised by the accumulation of toxic metabolites and hyperammonaemia related to secondary N-acetylglutamate deficiency. Carglumic acid, a synthetic analogue of N-acetylglutamate, decreases ammonia levels by restoring the functioning of the urea cycle. However, there are limited data available on the long-term safety and effectiveness of carglumic acid. Here, we present an interim analysis of the ongoing, long-term, prospective, observational PROTECT study (NCT04176523), which is investigating the long-term use of carglumic acid in children and adults with MMA and PA. Individuals with MMA or PA from France, Germany, Italy, Norway, Spain, Sweden and the UK who have received at least 1 year of carglumic acid treatment as part of their usual care are eligible for inclusion. The primary objective is the number and duration of acute metabolic decompensation events with hyperammonaemia (ammonia level >159 µmol/L during a patient's first month of life or >60 µmol/L thereafter, with an increased lactate level [> 1.8 mmol/L] and/or acidosis [pH < 7.35]) before and after treatment with carglumic acid. Peak plasma ammonia levels during the last decompensation event before and the first decompensation event after carglumic acid initiation, and the annualised rate of decompensation events before and after treatment initiation are also being assessed. Secondary objectives include the duration of hospital stay associated with decompensation events. Data are being collected at approximately 12 months' and 18 months' follow-up. Of the patients currently enrolled in the PROTECT study, data from ten available patients with MMA (n = 4) and PA (n = 6) were analysed. The patients had received carglumic acid for 14–77 (mean 36) months. Carglumic acid reduced the median peak ammonia level of the total patient population from 250 µmol/L (range 97–2569) before treatment to 103 µmol/L (range 97–171) after treatment. The annualised rate of acute metabolic decompensations with hyperammonaemia was reduced by a median of – 41% (range − 100% to + 60%) after treatment with carglumic acid. Of the five patients who experienced a decompensation event before treatment and for whom a post-treatment rate could be calculated, the annualised decompensation event rate was lower after carglumic acid treatment in four patients. The mean duration of hospital inpatient stay during decompensation events was shorter after than before carglumic acid treatment initiation in four of five patients for whom length of stay could be calculated. In this group of patients with MMA and PA, treatment with carglumic acid for at least 1 year reduced peak plasma ammonia levels in the total patient population and reduced the frequency of metabolic decompensation events, as well as the duration of inpatient stay due to metabolic decompensations in a subset of patients. ClinicalTrials.gov, NCT04176523. Registered 25 November, 2019, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04176523 .
2023-09-01 | Evaluation of the Neurodevelopmental Status for Urea Cycle Disorders: Based on Clinical Experience
Aim: Urea cycle disorders (UCD) still have poor neurological outcomes despite early diagnosis and treatment.We aimed to present the neurological outcomes of UCD patients and to determine the main simple and accessible factors affecting these outcomes. Materials and Methods:This was a descriptive cross-sectional study conducted in two pediatric metabolism centers on 29 patients from 25 unrelated families who were diagnosed and followed with UCD based on clinical presentation, neurological parameters, biochemical measurements, and molecular analysis.Results: Within the study population, the most common diagnosis was argininosuccinate synthase deficiency in 13 (44.82%)patients, followed by N-acetylglutamate synthase deficiency in five patients (17.24%), ornithine transcarbamylase deficiency in four patients (13.79%), arginase 1 deficiency in three patients (10.34%), carbamoyl phosphate synthase 1 deficiency in three patients (10.34%), and argininosuccinate lyase deficiency in one patient (3.44%).Peak ammonia levels were observed to be significantly higher in those patients with delayed milestones and patients who had Denver II <-2 standard deviation score results (p=0.032,p=0.026).Effect sizes were large in both groups.Delayed milestones were noted in 17 (94.4%) of the cases with peak ammonia >500 μmol/L (n=18).Those patients with abnormal neurological parameters had a significantly higher mean number of hyperammonemic episodes per year.Extracorporeal detoxification was given to eight patients, in combination with therapeutic hypothermia in two patients.Rapid regression was observed in brain edema in those who underwent therapeutic hypothermia. Conclusion:Our study emphasizes the effect of peak ammonia levels and the frequency of hyperammonemic episodes on neurological outcomes.There were still poor neurocognitive outcomes despite extracorporeal detoxification.This highlights the need to reassess current treatment strategies, including the threshold for starting extracorporeal detoxification if ammonia levels exceed 500 μmol/L.The use of therapeutic hypothermia by experienced teams may be promising due to its brain edema-reducing effects.
2022-09-05 | O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis
Abstract Life-threatening hyperammonemia occurs in both inherited and acquired liver diseases affecting ureagenesis, the main pathway for detoxification of neurotoxic ammonia in mammals. Protein O-GlcNAcylation is a reversible and nutrient-sensitive post-translational modification using as substrate UDP-GlcNAc, the end-product of hexosamine biosynthesis pathway. Here we show that increased liver UDP-GlcNAc during hyperammonemia increases protein O-GlcNAcylation and enhances ureagenesis. Mechanistically, O-GlcNAcylation on specific threonine residues increased the catalytic efficiency for ammonia of carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting enzyme in ureagenesis. Pharmacological inhibition of O-GlcNAcase, the enzyme removing O-GlcNAc from proteins, resulted in clinically relevant reductions of systemic ammonia in both genetic (hypomorphic mouse model of propionic acidemia) and acquired (thioacetamide-induced acute liver failure) mouse models of liver diseases. In conclusion, by fine-tuned control of ammonia entry into ureagenesis, hepatic O-GlcNAcylation of CPS1 increases ammonia detoxification and is a novel target for therapy of hyperammonemia in both genetic and acquired diseases.
2018-09-10 | Pharmacologic rescue of hyperammonemia-induced toxicity in zebrafish by inhibition of ornithine aminotransferase
Hyperammonemia is the common biochemical hallmark of urea cycle disorders, activating neurotoxic pathways. If untreated, affected individuals have a high risk of irreversible brain damage and mortality. Here we show that acute hyperammonemia strongly enhances transamination-dependent formation of osmolytic glutamine and excitatory glutamate, thereby inducing neurotoxicity and death in ammoniotelic zebrafish larvae via synergistically acting overactivation of NMDA receptors and bioenergetic impairment induced by depletion of 2-oxoglutarate. Intriguingly, specific and irreversible inhibition of ornithine aminotransferase (OAT) by 5-fluoromethylornithine rescues zebrafish from lethal concentrations of ammonium acetate and corrects hyperammonemia-induced biochemical alterations. Thus, OAT inhibition is a promising and effective therapeutic approach for preventing neurotoxicity and mortality in acute hyperammonemia.
cell therapies
2022-09-26 | Modelling urea cycle disorders using iPSCs
Abstract The urea cycle is a liver-based pathway enabling disposal of nitrogen waste. Urea cycle disorders (UCDs) are inherited metabolic diseases caused by deficiency of enzymes or transporters involved in the urea cycle and have a prevalence of 1:35,000 live births. Patients present recurrent acute hyperammonaemia, which causes high rate of death and neurological sequelae. Long-term therapy relies on a protein-restricted diet and ammonia scavenger drugs. Currently, liver transplantation is the only cure. Hence, high unmet needs require the identification of effective methods to model these diseases to generate innovative therapeutics. Advances in both induced pluripotent stem cells (iPSCs) and genome editing technologies have provided an invaluable opportunity to model patient-specific phenotypes in vitro by creating patients’ avatar models, to investigate the pathophysiology, uncover novel therapeutic targets and provide a platform for drug discovery. This review summarises the progress made thus far in generating 2- and 3-dimensional iPSCs models for UCDs, the challenges encountered and how iPSCs offer future avenues for innovation in developing the next-generation of therapies for UCDs.
small molecules
2026-01-01 | P047: Incidental identification of citrullinemia type 1 through carrier screening post liver transplant
Outcome and Follow-Up: Following the addition of carglumic acid, we were able to gradually wean our patient off all additional urea cycle disorder (UCD) management -ammonia scavengers and medical formula -over the course of five months.The patient has not experienced any further hyperammonemic episodes.Citrulline supplementation was discontinued at 11 months and plasma citrulline levels have remained normal to date.Glutamine and alanine levels have remained in normal range, with a maximum glutamine level of 671mol/L.At 21 months of age, the patient remains metabolically stable on carglumic acid 53.6mg/kg/day with dietary protein allotment not exceeding 2.2g/kg/day from intact protein without UCD formula.Developmentally he demonstrates mild-to-moderate delays; likely reflecting his hyperammonemia at presentation.Discussion: This case highlights the importance of early recognition and prompt initiation of carglumic acid in this diagnosis.The identified NAGS c.1289T>C variant adds to the catalog of pathogenic variants identified in this gene.Carglumic acid, an analog of N-acetylglutamate, has proven an effective sole treatment for this enzyme deficiency in our patient with sustained metabolic control.Conclusion: Early diagnosis and prompt initiation of carglumic acid therapy are lifesaving and life-altering in NAGS deficiency.This case contributes to the very limited clinical literature about this diagnosis and its long-term management, while adding to the clinical experience a novel variant.
2024-01-10 | Real-World Experience of Carglumic Acid for Methylmalonic and Propionic Acidurias: An Interim Analysis of the Multicentre Observational PROTECT Study
Methylmalonic aciduria (MMA) and propionic aciduria (PA) are organic acidurias characterised by the accumulation of toxic metabolites and hyperammonaemia related to secondary N-acetylglutamate deficiency. Carglumic acid, a synthetic analogue of N-acetylglutamate, decreases ammonia levels by restoring the functioning of the urea cycle. However, there are limited data available on the long-term safety and effectiveness of carglumic acid. Here, we present an interim analysis of the ongoing, long-term, prospective, observational PROTECT study (NCT04176523), which is investigating the long-term use of carglumic acid in children and adults with MMA and PA. Individuals with MMA or PA from France, Germany, Italy, Norway, Spain, Sweden and the UK who have received at least 1 year of carglumic acid treatment as part of their usual care are eligible for inclusion. The primary objective is the number and duration of acute metabolic decompensation events with hyperammonaemia (ammonia level >159 µmol/L during a patient's first month of life or >60 µmol/L thereafter, with an increased lactate level [> 1.8 mmol/L] and/or acidosis [pH < 7.35]) before and after treatment with carglumic acid. Peak plasma ammonia levels during the last decompensation event before and the first decompensation event after carglumic acid initiation, and the annualised rate of decompensation events before and after treatment initiation are also being assessed. Secondary objectives include the duration of hospital stay associated with decompensation events. Data are being collected at approximately 12 months' and 18 months' follow-up. Of the patients currently enrolled in the PROTECT study, data from ten available patients with MMA (n = 4) and PA (n = 6) were analysed. The patients had received carglumic acid for 14–77 (mean 36) months. Carglumic acid reduced the median peak ammonia level of the total patient population from 250 µmol/L (range 97–2569) before treatment to 103 µmol/L (range 97–171) after treatment. The annualised rate of acute metabolic decompensations with hyperammonaemia was reduced by a median of – 41% (range − 100% to + 60%) after treatment with carglumic acid. Of the five patients who experienced a decompensation event before treatment and for whom a post-treatment rate could be calculated, the annualised decompensation event rate was lower after carglumic acid treatment in four patients. The mean duration of hospital inpatient stay during decompensation events was shorter after than before carglumic acid treatment initiation in four of five patients for whom length of stay could be calculated. In this group of patients with MMA and PA, treatment with carglumic acid for at least 1 year reduced peak plasma ammonia levels in the total patient population and reduced the frequency of metabolic decompensation events, as well as the duration of inpatient stay due to metabolic decompensations in a subset of patients. ClinicalTrials.gov, NCT04176523. Registered 25 November, 2019, retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04176523 .
2023-09-01 | Evaluation of the Neurodevelopmental Status for Urea Cycle Disorders: Based on Clinical Experience
Aim: Urea cycle disorders (UCD) still have poor neurological outcomes despite early diagnosis and treatment.We aimed to present the neurological outcomes of UCD patients and to determine the main simple and accessible factors affecting these outcomes. Materials and Methods:This was a descriptive cross-sectional study conducted in two pediatric metabolism centers on 29 patients from 25 unrelated families who were diagnosed and followed with UCD based on clinical presentation, neurological parameters, biochemical measurements, and molecular analysis.Results: Within the study population, the most common diagnosis was argininosuccinate synthase deficiency in 13 (44.82%)patients, followed by N-acetylglutamate synthase deficiency in five patients (17.24%), ornithine transcarbamylase deficiency in four patients (13.79%), arginase 1 deficiency in three patients (10.34%), carbamoyl phosphate synthase 1 deficiency in three patients (10.34%), and argininosuccinate lyase deficiency in one patient (3.44%).Peak ammonia levels were observed to be significantly higher in those patients with delayed milestones and patients who had Denver II <-2 standard deviation score results (p=0.032,p=0.026).Effect sizes were large in both groups.Delayed milestones were noted in 17 (94.4%) of the cases with peak ammonia >500 μmol/L (n=18).Those patients with abnormal neurological parameters had a significantly higher mean number of hyperammonemic episodes per year.Extracorporeal detoxification was given to eight patients, in combination with therapeutic hypothermia in two patients.Rapid regression was observed in brain edema in those who underwent therapeutic hypothermia. Conclusion:Our study emphasizes the effect of peak ammonia levels and the frequency of hyperammonemic episodes on neurological outcomes.There were still poor neurocognitive outcomes despite extracorporeal detoxification.This highlights the need to reassess current treatment strategies, including the threshold for starting extracorporeal detoxification if ammonia levels exceed 500 μmol/L.The use of therapeutic hypothermia by experienced teams may be promising due to its brain edema-reducing effects.
2022-09-05 | O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis
Abstract Life-threatening hyperammonemia occurs in both inherited and acquired liver diseases affecting ureagenesis, the main pathway for detoxification of neurotoxic ammonia in mammals. Protein O-GlcNAcylation is a reversible and nutrient-sensitive post-translational modification using as substrate UDP-GlcNAc, the end-product of hexosamine biosynthesis pathway. Here we show that increased liver UDP-GlcNAc during hyperammonemia increases protein O-GlcNAcylation and enhances ureagenesis. Mechanistically, O-GlcNAcylation on specific threonine residues increased the catalytic efficiency for ammonia of carbamoyl phosphate synthetase 1 (CPS1), the rate-limiting enzyme in ureagenesis. Pharmacological inhibition of O-GlcNAcase, the enzyme removing O-GlcNAc from proteins, resulted in clinically relevant reductions of systemic ammonia in both genetic (hypomorphic mouse model of propionic acidemia) and acquired (thioacetamide-induced acute liver failure) mouse models of liver diseases. In conclusion, by fine-tuned control of ammonia entry into ureagenesis, hepatic O-GlcNAcylation of CPS1 increases ammonia detoxification and is a novel target for therapy of hyperammonemia in both genetic and acquired diseases.
2018-09-10 | Pharmacologic rescue of hyperammonemia-induced toxicity in zebrafish by inhibition of ornithine aminotransferase
Hyperammonemia is the common biochemical hallmark of urea cycle disorders, activating neurotoxic pathways. If untreated, affected individuals have a high risk of irreversible brain damage and mortality. Here we show that acute hyperammonemia strongly enhances transamination-dependent formation of osmolytic glutamine and excitatory glutamate, thereby inducing neurotoxicity and death in ammoniotelic zebrafish larvae via synergistically acting overactivation of NMDA receptors and bioenergetic impairment induced by depletion of 2-oxoglutarate. Intriguingly, specific and irreversible inhibition of ornithine aminotransferase (OAT) by 5-fluoromethylornithine rescues zebrafish from lethal concentrations of ammonium acetate and corrects hyperammonemia-induced biochemical alterations. Thus, OAT inhibition is a promising and effective therapeutic approach for preventing neurotoxicity and mortality in acute hyperammonemia.
cell therapies
2022-09-26 | Modelling urea cycle disorders using iPSCs
Abstract The urea cycle is a liver-based pathway enabling disposal of nitrogen waste. Urea cycle disorders (UCDs) are inherited metabolic diseases caused by deficiency of enzymes or transporters involved in the urea cycle and have a prevalence of 1:35,000 live births. Patients present recurrent acute hyperammonaemia, which causes high rate of death and neurological sequelae. Long-term therapy relies on a protein-restricted diet and ammonia scavenger drugs. Currently, liver transplantation is the only cure. Hence, high unmet needs require the identification of effective methods to model these diseases to generate innovative therapeutics. Advances in both induced pluripotent stem cells (iPSCs) and genome editing technologies have provided an invaluable opportunity to model patient-specific phenotypes in vitro by creating patients’ avatar models, to investigate the pathophysiology, uncover novel therapeutic targets and provide a platform for drug discovery. This review summarises the progress made thus far in generating 2- and 3-dimensional iPSCs models for UCDs, the challenges encountered and how iPSCs offer future avenues for innovation in developing the next-generation of therapies for UCDs.
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Drug Discovery Landscape
5 orphan drug designations for Hyperammonemia due to N-acetylglutamate synthase deficiency, including 1 approved therapy.
5 orphan drug designations for Hyperammonemia due to N-acetylglutamate synthase deficiency, including 1 approved therapy.
Drug | Therapy type | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
citric acid | small molecules | FDA | — | GENFIT SA |
Sodium benzoate | small molecules | EMA | — | Lucane Pharma SA |
Heterologous human adult liver-derived progenitor cells | cell therapies | EMA | — | Cellaion |
Carglumic acid [Carbaglu] | small molecules | EMA | — | Orphan Europe |
carglumic acid [Carbaglu] | small molecules | FDA | Approved | Orphan Europe SARL |
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