RARE DISEASE
Citrullinemia type I
Citrullinemia type I
Citrullinemia type I
Synonyms: ASS deficiency, Argininosuccinate synthase deficiency, Argininosuccinate synthetase deficiency, Argininosuccinic acid synthase deficiency, Argininosuccinic acid synthetase deficiency, CTLN1, Citrullinemia type 1, Classic citrullinemia
Synonyms: ASS deficiency, Argininosuccinate synthase deficiency, Argininosuccinate synthetase deficiency, Argininosuccinic acid synthase deficiency, Argininosuccinic acid synthetase deficiency, CTLN1, Citrullinemia type 1, Classic citrullinemia
Synonyms: ASS deficiency, Argininosuccinate synthase deficiency, Argininosuccinate synthetase deficiency, Argininosuccinic acid synthase deficiency, Argininosuccinic acid synthetase deficiency, CTLN1, Citrullinemia type 1, Classic citrullinemia
Drug discovery
4
drugs
With orphan designations
Overview
Citrullinemia type I (CTLN1) is a rare autosomal recessive urea cycle disorder caused by ASS1 gene mutations, leading to argininosuccinate synthase deficiency. This results in impaired ammonia detoxification, causing hyperammonemia, elevated citrulline, and neurotoxic effects. Neonatal-onset presents with rapid deterioration (lethargy, seizures, coma), while late-onset variants manifest with episodic hyperammonemic crises. Diagnosis relies on newborn screening (elevated citrulline) and genetic testing. Management involves acute ammonia reduction (scavengers, dialysis) and chronic protein restriction with nitrogen-scavenging therapies [1][3][15].
Categories: rare genetic diseases, rare inborn errors of metabolism
Research Papers
124 drug discovery papers about Citrullinemia type I, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
124 drug discovery papers about Citrullinemia type I, with 3 first-in-class and 1 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
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.
2026-02-28 | Dual rare genetic variants: case report of a child with SBIDDS syndrome and citrullinemia type 1.
BACKGROUND: The arginine methyltransferase 7 (PRMT7) gene plays a role in signal transduction and protein interactions and negatively regulates neuronal differentiation. Pathogenic variants of PRMT7 cause SBIDDS syndrome (Short stature, brachydactyly, intellectual developmental disability, and seizures). PRMT7 has been shown to interact with the argininosuccinate synthetase (ASS1) gene; biallelic pathogenic variants of ASS1 are associated with citrullinemia type 1. We report a patient with biallelic variants for SBIDDS syndrome and citrullinemia type 1. CASE PRESENTATION: The child exhibits severe intellectual disability, microcephaly, dysmorphisms, and seizures, consistent with the characteristics of these conditions. Exome sequencing identified variants c.1575 +1 G > A and c.232 dupT;p.Leu78Phefs*24 (NM_019023) in compound heterozygosity in the PRMT7 gene and variants c.1168G > A;p.Gly390Arg and c.-5-10C > G in exon 3 of the ASS1 gene (previously also identified in neonatal metabolic screening). The patient also has Wolf-Parkinson-White syndrome (WPW), behavioral issues, and brain morphological abnormalities, features that are poorly described in prior studies. CONCLUSIONS: It is not yet clear whether the clinical severity observed in this patient could also be partially due to interactions between these variants, as such interactions are not well-documented in the literature. Further research is necessary to elucidate the interplay between these two genes.
2026-01-01 | Fatal Neonatal Citrullinemia Type I Unmasking a History of Recurrent Reproductive Loss in a Non-Consanguineous Indian Family: A Case Report
This case report describes a fatal neonatal presentation of Citrullinemia Type I (CTLN1) in a term male infant from a non-consanguineous Indian family, a diagnosis that eventually provided an explanation for a significant history of recurrent reproductive loss (G6P2A4L0). The neonate initially manifested with refractory hypoglycemia at 10 hours of life, necessitating glucose infusion rates up to 13~mg/kg/min$, before progressing to severe hyperammonemic encephalopathy with a peak ammonia level of 1280~\mu mol/L$. Despite intensive supportive care, the infant died on day 15; however, postmortem tandem mass spectrometry revealed a diagnostic citrulline elevation of 1100~\mu mol/L, and whole exome sequencing identified a homozygous pathogenic splice-site variant in the ASS1 gene (c.421-2A>G). The case underscores the critical need for expedited newborn screening infrastructure in India, as the 20-day turnaround for biochemical results arrived only after the patient’s death, while highlighting how community endogamy can mimic consanguinity to facilitate rare autosomal recessive disorders
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.
2025-09-20 | Functional Profiling of 2,193 ASS1 Missense Variants: Insights into Variant Pathogenicity and Epistatic Interactions in Citrullinemia Type I
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 2193 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, supporting their clinical interpretation and diagnostic utility. 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.
2026-05-13 | 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.
2026-02-28 | Dual rare genetic variants: case report of a child with SBIDDS syndrome and citrullinemia type 1.
BACKGROUND: The arginine methyltransferase 7 (PRMT7) gene plays a role in signal transduction and protein interactions and negatively regulates neuronal differentiation. Pathogenic variants of PRMT7 cause SBIDDS syndrome (Short stature, brachydactyly, intellectual developmental disability, and seizures). PRMT7 has been shown to interact with the argininosuccinate synthetase (ASS1) gene; biallelic pathogenic variants of ASS1 are associated with citrullinemia type 1. We report a patient with biallelic variants for SBIDDS syndrome and citrullinemia type 1. CASE PRESENTATION: The child exhibits severe intellectual disability, microcephaly, dysmorphisms, and seizures, consistent with the characteristics of these conditions. Exome sequencing identified variants c.1575 +1 G > A and c.232 dupT;p.Leu78Phefs*24 (NM_019023) in compound heterozygosity in the PRMT7 gene and variants c.1168G > A;p.Gly390Arg and c.-5-10C > G in exon 3 of the ASS1 gene (previously also identified in neonatal metabolic screening). The patient also has Wolf-Parkinson-White syndrome (WPW), behavioral issues, and brain morphological abnormalities, features that are poorly described in prior studies. CONCLUSIONS: It is not yet clear whether the clinical severity observed in this patient could also be partially due to interactions between these variants, as such interactions are not well-documented in the literature. Further research is necessary to elucidate the interplay between these two genes.
2026-01-01 | Fatal Neonatal Citrullinemia Type I Unmasking a History of Recurrent Reproductive Loss in a Non-Consanguineous Indian Family: A Case Report
This case report describes a fatal neonatal presentation of Citrullinemia Type I (CTLN1) in a term male infant from a non-consanguineous Indian family, a diagnosis that eventually provided an explanation for a significant history of recurrent reproductive loss (G6P2A4L0). The neonate initially manifested with refractory hypoglycemia at 10 hours of life, necessitating glucose infusion rates up to 13~mg/kg/min$, before progressing to severe hyperammonemic encephalopathy with a peak ammonia level of 1280~\mu mol/L$. Despite intensive supportive care, the infant died on day 15; however, postmortem tandem mass spectrometry revealed a diagnostic citrulline elevation of 1100~\mu mol/L, and whole exome sequencing identified a homozygous pathogenic splice-site variant in the ASS1 gene (c.421-2A>G). The case underscores the critical need for expedited newborn screening infrastructure in India, as the 20-day turnaround for biochemical results arrived only after the patient’s death, while highlighting how community endogamy can mimic consanguinity to facilitate rare autosomal recessive disorders
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.
2025-09-20 | Functional Profiling of 2,193 ASS1 Missense Variants: Insights into Variant Pathogenicity and Epistatic Interactions in Citrullinemia Type I
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 2193 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, supporting their clinical interpretation and diagnostic utility. 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.
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Drug Discovery Landscape
4 orphan drug designations for Citrullinemia type I, including 1 approved therapy.
4 orphan drug designations for Citrullinemia type I, including 1 approved therapy.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Sodium benzoate, sodium phenylacetate | small molecules | EMA | 2019-05-29 | — | Dipharma B.V. |
Sodium phenylbutyrate [Pheburane] | small molecules | EMA | 2012-02-09 | — | Lucane Pharma |
Human heterologous liver cells (for infusion) | cell therapies | EMA | 2010-12-17 | — | Promethera Biosciences |
Glyceryl tri-(4-phenylbutyrate) [Ravicti] | small molecules | EMA | 2010-06-10 | 2015-12-01 | Immedica Pharma AB |
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