RARE DISEASE
Citrullinemia
Citrullinemia
Citrullinemia
Drug discovery
2
drugs
With orphan designations
Overview
Citrullinemia is an autosomal recessive urea cycle disorder characterized by toxic ammonia accumulation due to impaired argininosuccinate synthetase (type I) or citrin transporter (type II). Neonatal type I presents with hyperammonemia, lethargy, seizures, and coma, while type II often manifests in adulthood with neuropsychiatric symptoms. Diagnosis involves elevated plasma citrulline and genetic testing. Management includes dietary modifications, ammonia scavengers, and liver transplantation. Long-term complications include intellectual disability and hepatic dysfunction [1][3][11][14].
Burden
Neonatal type I mortality reaches 20% in developed nations despite treatment [4][12].
Chronic neurocognitive deficits, growth impairment, and recurrent hyperammonemic crises necessitate lifelong monitoring [9][11][19].
Liver transplantation remains the only cure but carries surgical risks and requires immunosuppression [3][4].
Therapies
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
225 drug discovery papers about Citrullinemia, with 3 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
225 drug discovery papers about Citrullinemia, with 3 first-in-class and 7 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-06-17 |
Twist variant codon usage for yeast.
Sequence variants in the urea cycle gene argininosuccinate synthase (ASS1) cause Citrullinemia type 1 (CTLN1), a rare autosomal recessive disease. Mechanistically, reduction in argininosuccinate synthetase (ASS) enzyme activity impairs the urea cycle, leading to an accumulation of citrulline and neurotoxic ammonia. Disease severity varies according to the degree of enzyme impairment, ranging from severe neonatal forms (classic citrullinemia) to milder, late-onset forms that may manifest in childhood or adulthood. We established a high-throughput yeast functional assay of human ASS and individually measured the impact of 2,193 amino acid substitutions, representing 90% of all single nucleotide variant (SNV)-accessible substitutions. When benchmarked against existing clinical variant annotation, our assay distinguishes known benign variants from strong loss of function pathogenic variants, enabling identification of a functional score threshold below which variants show clinically relevant impairment of ASS activity. Using the ACMG OddsPath framework, our assay meets PS3_supporting criteria for pathogenicity classification and achieves full PS3-level strength when variants observed as homozygotes in other primates are used as benign proxies for calibration. These results provide direct functional evidence to inform reclassification of ASS1 missense variants. Under the current ACMG guidelines, inclusion of our data yielded definitive classifications (pathogenic or likely pathogenic) for all 25 ClinVar VUS falling in the functionally impaired range of our assay. Mapping functional scores onto the protein structure, we confirmed that residues involved in catalysis are highly sensitive to substitution. In addition, we identified residues from adjacent subunits of the ASS homotetramer that form compound active sites. Assaying these positions revealed a capacity for intragenic complementation consistent with a variant sequestration model: a form of positive epistasis in which deleterious variants from different subunits are sequestered into only a subset of active sites, restoring function in the remaining variant-free sites. The discovery of intragenic complementation in ASS reveals a novel mode of functional interaction with clinical implications for interpreting variant combinations in heterozygous individuals.
2026-06-04 | Sudden Acute Liver Failure in Citrullinemia Type 1: An Argument for Earlier Liver Transplantation?
Acute liver failure has been described at initial presentation of citrullinemia type 1, but recurrent hepatic decompensations during medical treatment have not been reported. We describe 5 children developing episodes of acute liver failure, including one who required emergency liver transplantation. Our findings expand the citrullinemia type 1 phenotype and support early liver transplant referral in selected cases.
2026-05-13 | RNA-LNP-mediated in vivo prime editing corrects disease phenotypes in a mouse model of citrullinemia type I.
Citrullinemia type I (CTLN1) is a severe urea cycle disorder caused by pathogenic variants in the ASS1 (argininosuccinate synthetase 1) gene, for which liver transplantation remains the only curative option. Here, we used prime editing to correct the Ass1fold mouse model of CTLN1. Adeno-associated virus (AAV)-mediated delivery of the PE7 prime editor with an optimized prime editing guide RNA (pegRNA) achieved 71 and 54% correction of the pathogenic Ass1 mutation in hepatocytes of neonates and juveniles, respectively. Delivery of mRNA-encoded PE7 and synthetic pegRNA via lipid nanoparticles (LNPs) resulted in 24% correction after a single 3 mg kg-1 dose in neonates and 13% after three 4 mg kg-1 doses in juveniles. All treated groups showed full normalization of survival and of blood citrulline and ammonia concentrations, with restored urea cycle function and correction of natural behavior defects. Consistent with these findings, immunostaining demonstrated restoration of wild-type-like ASS1 protein localization in functionally relevant periportal and intermediate-zone hepatocytes. Editing was confined to the liver, with minimal indel formation and off-target activity and only transient elevations in liver enzymes. In a cellular reporter system, 6 of 15 recurrent human pathogenic ASS1 mutations studied, including the most common ASS1G390R variant, were corrected with similar or higher efficiencies than Ass1fold. These findings highlight prime editing as a precise and potentially curative treatment strategy for individuals with CTLN1 and other genetic liver diseases.
2026-03-19 | Impact of long-term nitrogen scavenger therapy on clinical outcome in individuals with urea cycle disorders.
Principles of long-term medical management in individuals with urea cycle disorders (UCDs) encompass (1) a low protein diet, (2) supplementation of arginine and/or citrulline along with essential amino acids, nutrients, vitamins and trace elements, and (3) use of nitrogen scavenging agents to reduce recurrent hyperammonemic events (HAEs). These principles aim at providing metabolic stability, elimimation of chronic complications, and achievement of normal development as well as growth. A retrospective comparative analysis was performed by studying 138 individuals with male ornithine transcarbamylase deficiency (mOTC-D), citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) based on in vitro residual enzymatic activity for severity-adjustment. Results show that individuals with mOTC-D, CTLN1 and ASA are at risk of progressive linear growth impairment, recurrent annual HAEs and an unfavorable neurocognitive outcome despite being under long-term nitrogen scavenging pharmacotherapy. No overall superiority among existing nitrogen scavenging agents with regard to the individual's metabolic stability, linear growth impairment and poor neurocognitive outcome was observed. Novel therapeutic strategies are urgently needed to ultimately improve health outcomes in individuals with UCDs in order to sufficiently meet guideline-specific goals.
2026-03-11 | Looking Beyond Severe Hypertriglyceridemia when Diagnosing Adult-Onset Citrullinemia Type II.
Adult-onset citrullinemia type II (CTLN2) is a rare autosomal recessive urea cycle disorder caused by mutations in the solute carrier family 25 member 13 (SLC25A13) gene, which encodes citrin-a mitochondrial transporter involved in the malate-aspartate shuttle. In adults, CTLN2 may present atypically as isolated hypertriglyceridemia, often misattributed to secondary dyslipidaemia. A 30-year-old Vietnamese male with longstanding severe hypertriglyceridemia, first identified at age 13, was referred after an episode of acute pancreatitis at age 28. At presentation, plasma triglyceride levels reached 34.61 mmol/l. Secondary causes were excluded. Genetic testing via next-generation sequencing revealed compound heterozygous SLC25A13 mutations: c.2T>C and c.1638_1660dup, resulting in p.Met1Thr and p.Ala554GlyfsTer17, confirming the diagnosis of CTLN2. Initiation of a low-carbohydrate, high-protein, low-fat diet combined with fenofibrate (145 mg/day) led to a rapid reduction in triglyceride levels, normalizing within two weeks and remaining stable over three months. The treatment was well tolerated, with no reported adverse effects. CTLN2 should be considered in young adults with persistent, unexplained, and severe hypertriglyceridemia. Dietary modification constitutes the cornerstone of management, with fibrates playing a supportive role. Persistent, unexplained, and severe hypertriglyceridemia in young adults should prompt consideration of inherited metabolic disorders, including adult-onset citrullinemia type II (CTLN2).Genetic testing to detect compound heterozygous or homozygous SLC25A13 variants is essential for definitive diagnosis of CTLN2.In CTLN2, dietary management with a low-carbohydrate, high-protein, low-fat represents the cornerstone, with fibrates serving as adjunctive lipid-lowering therapy.
2026-06-17 |
Twist variant codon usage for yeast.
Sequence variants in the urea cycle gene argininosuccinate synthase (ASS1) cause Citrullinemia type 1 (CTLN1), a rare autosomal recessive disease. Mechanistically, reduction in argininosuccinate synthetase (ASS) enzyme activity impairs the urea cycle, leading to an accumulation of citrulline and neurotoxic ammonia. Disease severity varies according to the degree of enzyme impairment, ranging from severe neonatal forms (classic citrullinemia) to milder, late-onset forms that may manifest in childhood or adulthood. We established a high-throughput yeast functional assay of human ASS and individually measured the impact of 2,193 amino acid substitutions, representing 90% of all single nucleotide variant (SNV)-accessible substitutions. When benchmarked against existing clinical variant annotation, our assay distinguishes known benign variants from strong loss of function pathogenic variants, enabling identification of a functional score threshold below which variants show clinically relevant impairment of ASS activity. Using the ACMG OddsPath framework, our assay meets PS3_supporting criteria for pathogenicity classification and achieves full PS3-level strength when variants observed as homozygotes in other primates are used as benign proxies for calibration. These results provide direct functional evidence to inform reclassification of ASS1 missense variants. Under the current ACMG guidelines, inclusion of our data yielded definitive classifications (pathogenic or likely pathogenic) for all 25 ClinVar VUS falling in the functionally impaired range of our assay. Mapping functional scores onto the protein structure, we confirmed that residues involved in catalysis are highly sensitive to substitution. In addition, we identified residues from adjacent subunits of the ASS homotetramer that form compound active sites. Assaying these positions revealed a capacity for intragenic complementation consistent with a variant sequestration model: a form of positive epistasis in which deleterious variants from different subunits are sequestered into only a subset of active sites, restoring function in the remaining variant-free sites. The discovery of intragenic complementation in ASS reveals a novel mode of functional interaction with clinical implications for interpreting variant combinations in heterozygous individuals.
2026-06-04 | Sudden Acute Liver Failure in Citrullinemia Type 1: An Argument for Earlier Liver Transplantation?
Acute liver failure has been described at initial presentation of citrullinemia type 1, but recurrent hepatic decompensations during medical treatment have not been reported. We describe 5 children developing episodes of acute liver failure, including one who required emergency liver transplantation. Our findings expand the citrullinemia type 1 phenotype and support early liver transplant referral in selected cases.
2026-05-13 | RNA-LNP-mediated in vivo prime editing corrects disease phenotypes in a mouse model of citrullinemia type I.
Citrullinemia type I (CTLN1) is a severe urea cycle disorder caused by pathogenic variants in the ASS1 (argininosuccinate synthetase 1) gene, for which liver transplantation remains the only curative option. Here, we used prime editing to correct the Ass1fold mouse model of CTLN1. Adeno-associated virus (AAV)-mediated delivery of the PE7 prime editor with an optimized prime editing guide RNA (pegRNA) achieved 71 and 54% correction of the pathogenic Ass1 mutation in hepatocytes of neonates and juveniles, respectively. Delivery of mRNA-encoded PE7 and synthetic pegRNA via lipid nanoparticles (LNPs) resulted in 24% correction after a single 3 mg kg-1 dose in neonates and 13% after three 4 mg kg-1 doses in juveniles. All treated groups showed full normalization of survival and of blood citrulline and ammonia concentrations, with restored urea cycle function and correction of natural behavior defects. Consistent with these findings, immunostaining demonstrated restoration of wild-type-like ASS1 protein localization in functionally relevant periportal and intermediate-zone hepatocytes. Editing was confined to the liver, with minimal indel formation and off-target activity and only transient elevations in liver enzymes. In a cellular reporter system, 6 of 15 recurrent human pathogenic ASS1 mutations studied, including the most common ASS1G390R variant, were corrected with similar or higher efficiencies than Ass1fold. These findings highlight prime editing as a precise and potentially curative treatment strategy for individuals with CTLN1 and other genetic liver diseases.
2026-03-19 | Impact of long-term nitrogen scavenger therapy on clinical outcome in individuals with urea cycle disorders.
Principles of long-term medical management in individuals with urea cycle disorders (UCDs) encompass (1) a low protein diet, (2) supplementation of arginine and/or citrulline along with essential amino acids, nutrients, vitamins and trace elements, and (3) use of nitrogen scavenging agents to reduce recurrent hyperammonemic events (HAEs). These principles aim at providing metabolic stability, elimimation of chronic complications, and achievement of normal development as well as growth. A retrospective comparative analysis was performed by studying 138 individuals with male ornithine transcarbamylase deficiency (mOTC-D), citrullinemia type 1 (CTLN1) and argininosuccinic aciduria (ASA) based on in vitro residual enzymatic activity for severity-adjustment. Results show that individuals with mOTC-D, CTLN1 and ASA are at risk of progressive linear growth impairment, recurrent annual HAEs and an unfavorable neurocognitive outcome despite being under long-term nitrogen scavenging pharmacotherapy. No overall superiority among existing nitrogen scavenging agents with regard to the individual's metabolic stability, linear growth impairment and poor neurocognitive outcome was observed. Novel therapeutic strategies are urgently needed to ultimately improve health outcomes in individuals with UCDs in order to sufficiently meet guideline-specific goals.
2026-03-11 | Looking Beyond Severe Hypertriglyceridemia when Diagnosing Adult-Onset Citrullinemia Type II.
Adult-onset citrullinemia type II (CTLN2) is a rare autosomal recessive urea cycle disorder caused by mutations in the solute carrier family 25 member 13 (SLC25A13) gene, which encodes citrin-a mitochondrial transporter involved in the malate-aspartate shuttle. In adults, CTLN2 may present atypically as isolated hypertriglyceridemia, often misattributed to secondary dyslipidaemia. A 30-year-old Vietnamese male with longstanding severe hypertriglyceridemia, first identified at age 13, was referred after an episode of acute pancreatitis at age 28. At presentation, plasma triglyceride levels reached 34.61 mmol/l. Secondary causes were excluded. Genetic testing via next-generation sequencing revealed compound heterozygous SLC25A13 mutations: c.2T>C and c.1638_1660dup, resulting in p.Met1Thr and p.Ala554GlyfsTer17, confirming the diagnosis of CTLN2. Initiation of a low-carbohydrate, high-protein, low-fat diet combined with fenofibrate (145 mg/day) led to a rapid reduction in triglyceride levels, normalizing within two weeks and remaining stable over three months. The treatment was well tolerated, with no reported adverse effects. CTLN2 should be considered in young adults with persistent, unexplained, and severe hypertriglyceridemia. Dietary modification constitutes the cornerstone of management, with fibrates playing a supportive role. Persistent, unexplained, and severe hypertriglyceridemia in young adults should prompt consideration of inherited metabolic disorders, including adult-onset citrullinemia type II (CTLN2).Genetic testing to detect compound heterozygous or homozygous SLC25A13 variants is essential for definitive diagnosis of CTLN2.In CTLN2, dietary management with a low-carbohydrate, high-protein, low-fat represents the cornerstone, with fibrates serving as adjunctive lipid-lowering therapy.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
Drug Discovery Landscape
2 orphan drug designations for Citrullinemia.
2 orphan drug designations for Citrullinemia.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Sodium benzoate | small molecules | EMA | 2016-07-14 | — | Lucane Pharma SA |
Heterologous human adult liver-derived progenitor cells | cell therapies | EMA | 2013-07-17 | — | Cellaion |
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