RARE DISEASE
Disorder of asparagine metabolism
Disorder of asparagine metabolism
Disorder of asparagine metabolism
Drug discovery
0
drugs
With orphan designations
Overview
Asparagine synthetase deficiency (ASNSD) is a rare autosomal recessive neurometabolic disorder caused by ASNS gene mutations, impairing asparagine synthesis. It manifests as congenital microcephaly, severe developmental delay, intractable seizures, spastic quadriplegia, and progressive cerebral atrophy. Asparagine deficiency in the brain due to blood-brain barrier impermeability leads to profound neurological deterioration. Prognosis is poor, with most affected individuals not surviving past childhood [1][4][8][10].
Burden
Profound disability: Inability to walk, communicate, or perform self-care [1][4][10].
High care intensity: Requires lifelong multidisciplinary management (neurology, nutrition, rehabilitation) [8][16].
Mortality: Typically fatal in early childhood; significant emotional and financial strain on families [1][4][16].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
40 drug discovery papers about Disorder of asparagine metabolism, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
40 drug discovery papers about Disorder of asparagine metabolism, with 2 first-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-08 | Asparagine synthetase deficiency: clinical features and experience with asparagine supplementation.
Asparagine synthetase deficiency is a rare autosomal recessive neurometabolic disorder characterized by congenital and progressive microcephaly, severe developmental delay, epilepsy, and progressive cerebral atrophy. Therapeutic experience with L-asparagine supplementation remains limited and heterogeneous. We report a preterm female infant born to consanguineous parents who presented with congenital microcephaly and early-onset myoclonic epilepsy. During follow-up, diaphragmatic eventration was identified and contributed to recurrent episodes of respiratory failure. Metabolic screening studies were unremarkable; however, cerebrospinal fluid asparagine concentration was markedly reduced (4.42 μmol/L; reference range 8-34 μmol/L). Brain magnetic resonance imaging demonstrated cerebral atrophy with white matter involvement. Whole-exome sequencing identified a homozygous splice-site variant in the ASNS gene. Oral L-asparagine supplementation was initiated at 5 months of age (50 mg/kg/day and increased to 100 mg/kg/day after one week). A reduction in seizure frequency was observed following treatment initiation; however, this finding should be interpreted cautiously because it coincided with changes in antiepileptic therapy. No meaningful neurodevelopmental progress was observed during follow-up. ASNSD should be suspected in patients with progressive microcephaly and early-onset epilepsy despite normal metabolic screening, and CSF amino acid analysis is valuable for diagnosis. Although a reduction in seizure frequency was observed following L-asparagine supplementation in our patient, this finding should be interpreted cautiously because phenobarbital was discontinued and topiramate therapy was initiated during the same period. Therefore, the therapeutic efficacy of L-asparagine supplementation remains uncertain, and its impact on neurodevelopment appears limited.
2026-07-01 | Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.
Pathogenic alleles in the cytoplasmic asparaginyl-tRNA synthetase (NARS1) are associated with infant- and juvenile-onset disease, with no current disease-specific treatments. We developed a tractable human cell system to study disease-causing NARS1 alleles that can be adapted to investigate NARS1 and other aminoacyl-tRNA synthetase (ARS) alleles. We found that two dominant NARS1 nonsense alleles, R534X and R522X, cause a cytotoxic phenotype and elicit the integrated stress response (ISR). Proteomic and phenotypic changes were rescued by asparagine supplementation in the human cell model. Asparagine supplementation completely restored cell proliferation defects in patient-derived fibroblasts and prevented activation of the ISR. We also tested therapeutic cognate transfer RNA (tRNA) supplementation, which reduced the cytotoxicity of pathogenic NARS1 alleles but did not ameliorate activation of the ISR. A general control nonderepressible 2 (GCN2) inhibitor suppressed ISR activation and reduced cytotoxicity but did not restore changes to the proteome caused by the NARS1 nonsense alleles. The data reveal molecular and cellular defects caused by premature termination codons in NARS1 alleles. Our data also indicate asparagine supplementation as a feasible therapeutic approach to address the underlying cause of NARS1 disease, a rare disease for which currently no treatment is available.
2026-04-07 | Levan-derived oligosaccharides (LOS) prime barley against fungal pathogens through asparagine metabolism.
Overuse of chemical pesticides motivates green disease control strategy. Levan-derived oligosaccharides (LOS) are immune elicitors, but its structure information and underlying regulatory mechanisms remain unclear. In this study, LOS produced from sucrose using LevB1SacB fusion enzyme, was purified by CSR-1Na resin, and characterized by HPLC, ATR-FTIR and 1D/2D NMR. Foliar LOS spraying (0.5‰) enhanced barley resistance to Rhizoctonia solani and Pyrenophora graminea, reducing necrotic area by 60.5% and 22.4%, but had little effect on the hemibiotrophic pathogen Bipolaris sorokiniana of spot blotch. LOS itself did not inhibit fungal growth in vitro. LOS priming strengthened infection-triggered antioxidant and defense responses. RNA-seq analysis indicated pathogens but not LOS enhanced transcriptional reprogramming, with differential genes enriched in amino acid metabolism. Among transcriptome-guided candidates, HvAS1, an asparagine synthetase, was verified to participate in LOS-enhanced resistance: HvAS1 overexpression in Arabidopsis accumulated more asparagine and jasmonate after infection and reduced R. solani lesions by >50%, whereas virus-induced silencing in barley compromised resistance. Besides, foliar asparagine spraying also increased barley resistance to R. solani. Together, LOS acts as an efficient elicitor and reveals the link between amino acid metabolism and plant immunity.
2025-09-04 | Asparaginase and Autophagy Inhibitors Effectively Remove Senescent Cells by Synergistically Limiting Asparagine Supply.
The accumulation of senescent cells (SNCs) contributes to tissue dysfunction and age-related diseases, creating an urgent need for effective senolytic strategies. We identified a metabolic vulnerability in SNCs characterized by marked downregulation of asparagine synthetase (ASNS), rendering them uniquely dependent on exogenous asparagine (Asn). This vulnerability was exploited through combined treatment with L-asparaginase (ASNase) and autophagy inhibitors, which synergistically deplete Asn via complementary mechanisms: ASNase degrades extracellular Asn pools, while autophagy inhibition blocks intracellular protein recycling as an alternative Asn source. This dual approach induced selective synthetic lethality across multiple SNC types in vitro. In aged mice, the combination therapy significantly reduced SNC burden in diverse tissues, improved physiological function, and attenuated progression of age-related conditions including osteoporosis, atherosclerosis, and non-alcoholic fatty liver disease. Our findings establish concurrent targeting of extracellular and intracellular Asn supplies as a potent, selective senolytic strategy with broad therapeutic potential for age-related disorders.
2025-05-24 | Identification of 1,2,3,4,6-O-Pentagalloylglucose as a novel ASNS inhibitor for MASLD amelioration in mice by increasing l-aspartate levels alongside LKB1/AMPK metabolic axis activation.
l-aspartate is a nonessential amino acid involving tricarboxylic acid cycle, amplifying hepatic l-aspartate level is a practicable and promising therapeutic approach in treating metabolic dysfunction-associated steatotic liver disease (MASLD) and liver injury-induced liver fibrosis. However, fewer compounds have been reported to increase hepatic l-aspartate level for ameliorating MASLD in vivo. Asparagine synthetase (ASNS) catalyzes the conversion of l-aspartate into asparagine, here, we identified a natural molecule, named 1, 2, 3, 4,6-O-Pentagalloylglucose (PGG), from the compound library (∼7133 compounds) using the free energy perturbation (FEP)-based virtual screening strategy. PGG showed strong binding affinity (KD = 8.8 μM) against recombinant human ASNS and inhibited its enzymatic activity (IC50 = 7.1 μM), subsequently increased cellular l-aspartate level and activated LKB1/AMPK metabolic axis and enhanced lipid oxidation, leading to lipid accumulation suppression in hepatocytes. Correspondingly, treating PGG (10 mg/kg/per 2 days, i. p.) in mice for 6 weeks efficiently corrected high-fat and high-cholesterol (HFC) diet induced bodyweight gained, glucose tolerance impairment, insulin resistance, and all the typical manifestations of MASLD, including hepatic steatosis, liver injury, and inflammation. These therapeutics were associated with decreases in ASNS expression level in liver, leading to increases in hepatic l-aspartate level, activation of LKB1/AMPK axis, and improvement of mitochondrial oxidation. These data indicate that increasing hepatic l-aspartate level would be a promising therapeutic strategy in treating MASLD, and ASNS would be a novel target for developing anti-MASLD agents.
2026-08-08 | Asparagine synthetase deficiency: clinical features and experience with asparagine supplementation.
Asparagine synthetase deficiency is a rare autosomal recessive neurometabolic disorder characterized by congenital and progressive microcephaly, severe developmental delay, epilepsy, and progressive cerebral atrophy. Therapeutic experience with L-asparagine supplementation remains limited and heterogeneous. We report a preterm female infant born to consanguineous parents who presented with congenital microcephaly and early-onset myoclonic epilepsy. During follow-up, diaphragmatic eventration was identified and contributed to recurrent episodes of respiratory failure. Metabolic screening studies were unremarkable; however, cerebrospinal fluid asparagine concentration was markedly reduced (4.42 μmol/L; reference range 8-34 μmol/L). Brain magnetic resonance imaging demonstrated cerebral atrophy with white matter involvement. Whole-exome sequencing identified a homozygous splice-site variant in the ASNS gene. Oral L-asparagine supplementation was initiated at 5 months of age (50 mg/kg/day and increased to 100 mg/kg/day after one week). A reduction in seizure frequency was observed following treatment initiation; however, this finding should be interpreted cautiously because it coincided with changes in antiepileptic therapy. No meaningful neurodevelopmental progress was observed during follow-up. ASNSD should be suspected in patients with progressive microcephaly and early-onset epilepsy despite normal metabolic screening, and CSF amino acid analysis is valuable for diagnosis. Although a reduction in seizure frequency was observed following L-asparagine supplementation in our patient, this finding should be interpreted cautiously because phenobarbital was discontinued and topiramate therapy was initiated during the same period. Therefore, the therapeutic efficacy of L-asparagine supplementation remains uncertain, and its impact on neurodevelopment appears limited.
2026-07-01 | Therapeutic rescue of pathogenic asparaginyl-tRNA synthetase alleles.
Pathogenic alleles in the cytoplasmic asparaginyl-tRNA synthetase (NARS1) are associated with infant- and juvenile-onset disease, with no current disease-specific treatments. We developed a tractable human cell system to study disease-causing NARS1 alleles that can be adapted to investigate NARS1 and other aminoacyl-tRNA synthetase (ARS) alleles. We found that two dominant NARS1 nonsense alleles, R534X and R522X, cause a cytotoxic phenotype and elicit the integrated stress response (ISR). Proteomic and phenotypic changes were rescued by asparagine supplementation in the human cell model. Asparagine supplementation completely restored cell proliferation defects in patient-derived fibroblasts and prevented activation of the ISR. We also tested therapeutic cognate transfer RNA (tRNA) supplementation, which reduced the cytotoxicity of pathogenic NARS1 alleles but did not ameliorate activation of the ISR. A general control nonderepressible 2 (GCN2) inhibitor suppressed ISR activation and reduced cytotoxicity but did not restore changes to the proteome caused by the NARS1 nonsense alleles. The data reveal molecular and cellular defects caused by premature termination codons in NARS1 alleles. Our data also indicate asparagine supplementation as a feasible therapeutic approach to address the underlying cause of NARS1 disease, a rare disease for which currently no treatment is available.
2026-04-07 | Levan-derived oligosaccharides (LOS) prime barley against fungal pathogens through asparagine metabolism.
Overuse of chemical pesticides motivates green disease control strategy. Levan-derived oligosaccharides (LOS) are immune elicitors, but its structure information and underlying regulatory mechanisms remain unclear. In this study, LOS produced from sucrose using LevB1SacB fusion enzyme, was purified by CSR-1Na resin, and characterized by HPLC, ATR-FTIR and 1D/2D NMR. Foliar LOS spraying (0.5‰) enhanced barley resistance to Rhizoctonia solani and Pyrenophora graminea, reducing necrotic area by 60.5% and 22.4%, but had little effect on the hemibiotrophic pathogen Bipolaris sorokiniana of spot blotch. LOS itself did not inhibit fungal growth in vitro. LOS priming strengthened infection-triggered antioxidant and defense responses. RNA-seq analysis indicated pathogens but not LOS enhanced transcriptional reprogramming, with differential genes enriched in amino acid metabolism. Among transcriptome-guided candidates, HvAS1, an asparagine synthetase, was verified to participate in LOS-enhanced resistance: HvAS1 overexpression in Arabidopsis accumulated more asparagine and jasmonate after infection and reduced R. solani lesions by >50%, whereas virus-induced silencing in barley compromised resistance. Besides, foliar asparagine spraying also increased barley resistance to R. solani. Together, LOS acts as an efficient elicitor and reveals the link between amino acid metabolism and plant immunity.
2025-09-04 | Asparaginase and Autophagy Inhibitors Effectively Remove Senescent Cells by Synergistically Limiting Asparagine Supply.
The accumulation of senescent cells (SNCs) contributes to tissue dysfunction and age-related diseases, creating an urgent need for effective senolytic strategies. We identified a metabolic vulnerability in SNCs characterized by marked downregulation of asparagine synthetase (ASNS), rendering them uniquely dependent on exogenous asparagine (Asn). This vulnerability was exploited through combined treatment with L-asparaginase (ASNase) and autophagy inhibitors, which synergistically deplete Asn via complementary mechanisms: ASNase degrades extracellular Asn pools, while autophagy inhibition blocks intracellular protein recycling as an alternative Asn source. This dual approach induced selective synthetic lethality across multiple SNC types in vitro. In aged mice, the combination therapy significantly reduced SNC burden in diverse tissues, improved physiological function, and attenuated progression of age-related conditions including osteoporosis, atherosclerosis, and non-alcoholic fatty liver disease. Our findings establish concurrent targeting of extracellular and intracellular Asn supplies as a potent, selective senolytic strategy with broad therapeutic potential for age-related disorders.
2025-05-24 | Identification of 1,2,3,4,6-O-Pentagalloylglucose as a novel ASNS inhibitor for MASLD amelioration in mice by increasing l-aspartate levels alongside LKB1/AMPK metabolic axis activation.
l-aspartate is a nonessential amino acid involving tricarboxylic acid cycle, amplifying hepatic l-aspartate level is a practicable and promising therapeutic approach in treating metabolic dysfunction-associated steatotic liver disease (MASLD) and liver injury-induced liver fibrosis. However, fewer compounds have been reported to increase hepatic l-aspartate level for ameliorating MASLD in vivo. Asparagine synthetase (ASNS) catalyzes the conversion of l-aspartate into asparagine, here, we identified a natural molecule, named 1, 2, 3, 4,6-O-Pentagalloylglucose (PGG), from the compound library (∼7133 compounds) using the free energy perturbation (FEP)-based virtual screening strategy. PGG showed strong binding affinity (KD = 8.8 μM) against recombinant human ASNS and inhibited its enzymatic activity (IC50 = 7.1 μM), subsequently increased cellular l-aspartate level and activated LKB1/AMPK metabolic axis and enhanced lipid oxidation, leading to lipid accumulation suppression in hepatocytes. Correspondingly, treating PGG (10 mg/kg/per 2 days, i. p.) in mice for 6 weeks efficiently corrected high-fat and high-cholesterol (HFC) diet induced bodyweight gained, glucose tolerance impairment, insulin resistance, and all the typical manifestations of MASLD, including hepatic steatosis, liver injury, and inflammation. These therapeutics were associated with decreases in ASNS expression level in liver, leading to increases in hepatic l-aspartate level, activation of LKB1/AMPK axis, and improvement of mitochondrial oxidation. These data indicate that increasing hepatic l-aspartate level would be a promising therapeutic strategy in treating MASLD, and ASNS would be a novel target for developing anti-MASLD agents.
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