Home / Deep Research / Carbamoyl Phosphate Synthetase I Deficiency

Carbamoyl Phosphate Synthetase I Deficiency

Disease Pathophysiology Research Template

2026-02-23
Falcon MONDO:0009376 Model: Edison Scientific Literature 40 citations

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Pathophysiology Research Template

Target Disease

  • Disease Name: Carbamoyl Phosphate Synthetase I Deficiency
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on the pathophysiology of Carbamoyl Phosphate Synthetase I Deficiency. Focus on the molecular and cellular mechanisms underlying disease progression.

Required Information

1. Core Pathophysiology

  • What are the primary pathophysiological mechanisms?
  • What molecular pathways are dysregulated?
  • What cellular processes are affected?

2. Key Molecular Players

  • Genes/Proteins: Which genes are causally involved or implicated?
  • Chemical Entities: What metabolites, drugs, or small molecules are relevant?
  • Cell Types: Which cell types are primarily affected?
  • Anatomical Locations: Which tissues/organs are involved?

3. Biological Processes (for GO annotation)

  • What biological processes (GO terms) are disrupted?
  • Consider: signaling pathways, metabolic processes, cellular responses, transport, etc.

4. Cellular Components

  • Where in the cell do key processes occur?
  • Consider: organelles, membrane compartments, extracellular space, etc.

5. Disease Progression

  • What is the sequence of events from initial trigger to clinical manifestation?
  • Are there distinct stages or phases?

6. Phenotypic Manifestations

  • What are the key clinical phenotypes?
  • How do they relate to the underlying mechanisms?

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes where possible to support key statements

Output Format

Structure your response as a narrative that could be used to populate a disease knowledge base entry with: - Pathophysiology description - Gene/protein annotations with ontology terms (HGNC, GO) - Phenotype associations (HP terms) - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Evidence items with PMIDs

Title: Pathophysiology of Carbamoyl Phosphate Synthetase I (CPS1) Deficiency (Urea Cycle Disorder)

Publication focus: Molecular/cellular mechanisms, disease progression, and real-world management emphasizing 2023–2024 evidence.

Target disease - Disease name: Carbamoyl Phosphate Synthetase I Deficiency (CPS1D; OMIM 237300) - MONDO ID: Not identified from the retrieved evidence in this run (OpenTargets name resolution failed). - Category: Genetic (autosomal recessive)

  1. Key concepts and current understanding (definitions and core mechanisms)

1.1 Definition and primary biochemical lesion CPS1 deficiency is a proximal (mitochondrial) urea cycle disorder caused by loss-of-function or hypomorphic variants in CPS1, the enzyme catalyzing the first (rate-limiting) urea-cycle step: ATP-dependent condensation of ammonia and bicarbonate to carbamoyl phosphate in the mitochondrial matrix. Loss of CPS1 activity causes failure of hepatic ammonia detoxification to urea, leading to systemic hyperammonemia and downstream neurotoxicity. (noori2024carbamolyphosphatesynthetase1 pages 2-3, noori2024carbamolyphosphatesynthetase1 pages 1-2, dong2024clinicalfeaturesand pages 1-2)

The reaction is functionally dependent on N-acetylglutamate (NAG) as an essential allosteric activator; thus, disruptions upstream of NAG generation (e.g., NAGS deficiency) phenocopy CPS1 deficiency and are clinically indistinguishable without genetic/enzymatic discrimination. (erdal2025aminoacidmetabolism pages 10-12, shakerdi2023druginducedhyperammonaemia pages 1-2)

1.2 Characteristic biochemical pattern (diagnostic metabolic signature) Across contemporary clinical series and case reports, CPS1 deficiency produces a characteristic proximal-UCD biochemical profile: - Hyperammonemia - Decreased plasma citrulline - Elevated plasma glutamine - Low/absent urinary orotic acid (helps distinguish from OTC deficiency, where orotic acid is often elevated) For example, a recent adult CPS1D case report summarizes this “characteristic biochemical pattern” as “hyperammonemia, decreased plasma citrulline and elevated plasma glutamine,” and notes “absence of orotic acid excretion” supporting CPS1 deficiency. (yokota2025carbamoylphosphatesynthetase pages 2-3)

Noori et al. (2024) similarly describe hallmark findings of “severe hyperammonemia, low plasma citrulline, high plasma glutamine … and low urinary orotic acid.” (noori2024carbamolyphosphatesynthetase1 pages 2-3)

Some late-onset cases also show secondary amino-acid changes consistent with nitrogen handling and catabolic stress (e.g., elevated alanine). A 2023 adolescent-onset case reported ammonia 287 µmol/L, alanine 757 µmol/L (elevated), and citrulline 4.26 µmol/L (low), with urine orotic acid 0.0. (wang2023clinicalandgenetic pages 3-5)

1.3 Tissue/cell specificity and compartmentalization - Primary organ: liver (hepatocyte mitochondria). CPS1 is an intramitochondrial urea-cycle enzyme; failure of hepatic mitochondrial ureagenesis is the proximate driver of systemic hyperammonemia. (yokota2025carbamoylphosphatesynthetase pages 2-3, erdal2025aminoacidmetabolism pages 10-12) - Major vulnerable organ: brain. Hyperammonemia is specifically neurotoxic; in a 2023 clinical pathology review, “Ammonia is toxic to the brain but not to other tissues and readily crosses the blood-brain barrier.” (shakerdi2023druginducedhyperammonaemia pages 1-2) - Key brain cell type: astrocytes. Multiple sources support the canonical model in which detoxification of brain ammonia to glutamine in astrocytes drives osmotic stress and swelling: hyperammonemia may “lead to excessive glutamine glial accumulation leading to astrocyte swelling.” (shakerdi2023druginducedhyperammonaemia pages 1-2) A UCD overview states: “Acutely elevated ammonia concentration leads to increased glutamine content in astrocytes, causing them to swell,” contributing to cerebral edema. (simpson2025ureacycledisordersa pages 1-4)

1.4 Dysregulated molecular pathways and cellular processes Core dysregulated processes in CPS1D can be organized into: A. Nitrogen disposal failure and compensatory nitrogen storage - Failure of urea synthesis leads to accumulation of ammonia and compensatory nitrogen sequestration in glutamine (in plasma and brain). Plasma glutamine is used clinically as an index of total nitrogen load, and “the mainstay of treatment … is to prevent catabolism and control plasma glutamine.” (noori2024carbamolyphosphatesynthetase1 pages 1-2)

B. Hyperammonemia-driven neurotoxicity mechanisms Mechanisms supported in the retrieved sources include: - Astrocyte glutamine accumulation → astrocyte swelling → cerebral edema/raised intracranial pressure (shakerdi2023druginducedhyperammonaemia pages 1-2, simpson2025ureacycledisordersa pages 1-4) - Mitochondrial/energetic impairment: hyperammonemia “may interfere with mitochondrial function” (shakerdi2023druginducedhyperammonaemia pages 1-2) - Neurotransmission imbalance and seizures: UCD overview notes seizures can correlate with rising glutamine even before ammonia peaks (“These seizures may be seen during the rise of blood glutamine concentration even before blood ammonia concentrations peak”). (simpson2025ureacycledisordersa pages 1-4)

C. Mitochondrial regulation of urea-cycle entry via NAG NAG is a central regulatory metabolite. The hyperammonemia review states: “NAGS produces NAG which is an essential cofactor for CPSI, the first and rate-limiting enzyme of the urea cycle.” (shakerdi2023druginducedhyperammonaemia pages 1-2) A liver-mitochondria metabolism review similarly emphasizes CPS1 as the rate-limiting step and NAG as “an essential allosteric activator.” (erdal2025aminoacidmetabolism pages 10-12)

  1. Core pathophysiology (knowledge-base narrative)

2.1 Sequence of events from trigger to clinical manifestation A clinically useful mechanistic cascade for CPS1D is: 1) Genetic loss/reduction of CPS1 activity in hepatocyte mitochondria → impaired carbamoyl phosphate formation and impaired ureagenesis. (noori2024carbamolyphosphatesynthetase1 pages 2-3, erdal2025aminoacidmetabolism pages 10-12) 2) Systemic ammonia accumulation due to inability to convert waste nitrogen into urea; ammonia sources include amino-acid turnover and gut urease. (noori2024carbamolyphosphatesynthetase1 pages 1-2) 3) Compensatory nitrogen buffering as glutamine (plasma and brain), with low citrulline reflecting reduced flux through the proximal urea cycle. (yokota2025carbamoylphosphatesynthetase pages 2-3, noori2024carbamolyphosphatesynthetase1 pages 2-3) 4) CNS exposure: ammonia crosses the BBB (shakerdi2023druginducedhyperammonaemia pages 1-2), and astrocytic ammonia detoxification increases intracellular glutamine, causing osmotic swelling, cerebral edema, and encephalopathy. (shakerdi2023druginducedhyperammonaemia pages 1-2, simpson2025ureacycledisordersa pages 1-4) 5) Clinical decompensation: vomiting, lethargy, seizures, coma; neuroimaging may show white matter injury in late-onset presentations. (wang2023clinicalandgenetic pages 3-5, dong2024clinicalfeaturesand pages 1-2)

2.2 Disease stages / phenotypic strata (neonatal vs late onset) A consistent modern framework divides CPS1D into: - Neonatal-onset (severe, often within days): Noori et al. (2024) emphasize a neonatal phenotype with acute severe hyperammonemia and neurologic crisis (hypotonia, seizures, coma, death or neurologic sequelae). (noori2024carbamolyphosphatesynthetase1 pages 2-3) - Late-onset (residual activity): Adult/late-onset is “associated with some residual enzyme activity.” (yokota2025carbamoylphosphatesynthetase pages 2-3) Dong et al. (2024) describe late-onset cases presenting with “mental retardation, psychiatric symptoms, and self-selected low-protein diets.” (dong2024clinicalfeaturesand pages 1-2)

  1. Key molecular players (entities for mechanistic annotation)

3.1 Genes/proteins (causal) - CPS1 (carbamoyl-phosphate synthase 1; mitochondrial) — causal gene in CPS1 deficiency; extensive allelic heterogeneity with many novel variants reported in 2023–2024 cohorts. (wang2023clinicalandgenetic pages 3-5, dong2024clinicalfeaturesand pages 1-2)

3.2 Functionally linked genes/proteins (pathway context / differential diagnosis) - NAGS (N-acetylglutamate synthase) — produces N-acetylglutamate (NAG), an essential CPS1 activator; NAGS deficiency phenocopies CPS1D. (shakerdi2023druginducedhyperammonaemia pages 1-2, erdal2025aminoacidmetabolism pages 10-12)

3.3 Chemical entities (metabolites and therapeutic small molecules) Core disease-relevant metabolites - Ammonia (NH3/NH4+) — toxic metabolite; hyperammonemia drives neurologic injury. (shakerdi2023druginducedhyperammonaemia pages 1-2, noori2024carbamolyphosphatesynthetase1 pages 1-2) - Glutamine — major nitrogen carrier and biomarker (“plasma glutamine … index of total nitrogen load”). (noori2024carbamolyphosphatesynthetase1 pages 1-2, noori2024carbamolyphosphatesynthetase1 pages 2-3) - Citrulline — decreased in CPS1D (low plasma citrulline); supplemented therapeutically. (yokota2025carbamoylphosphatesynthetase pages 2-3, imbard2023citrullineinthe pages 1-2) - Orotic acid — typically absent/low urinary excretion in CPS1D; diagnostically helpful. (yokota2025carbamoylphosphatesynthetase pages 2-3, erdal2025aminoacidmetabolism pages 10-12) - Alanine — can be elevated in CPS1D (example in late-onset case). (wang2023clinicalandgenetic pages 3-5) - N-acetylglutamate (NAG) — essential activator of CPS1; functional deficiency exacerbates hyperammonemia. (shakerdi2023druginducedhyperammonaemia pages 1-2, erdal2025aminoacidmetabolism pages 10-12)

Therapeutic agents and relevant small molecules - Sodium phenylbutyrate / glycerol phenylbutyrate (nitrogen scavengers): “GPB and NaPBA are converted to phenylacetic acid (PAA) which when conjugated with glutamine forms phenylacetylglutamine (PAGN).” (glinton2023monitoringthetreatment pages 1-2) - Sodium benzoate (nitrogen scavenger). (noori2024carbamolyphosphatesynthetase1 pages 2-3, glinton2023monitoringthetreatment pages 1-2) - L-arginine and L-citrulline (urea-cycle intermediates / supplementation). (yokota2025carbamoylphosphatesynthetase pages 2-3, imbard2023citrullineinthe pages 1-2) - N-carbamyl-L-glutamate / N-carbamylglutamate (carglumic acid; NAG analog that activates CPS1): A UCD overview notes it “can restore urea cycle activity & normalize ammonia,” and that some individuals with CPS1D may benefit. (simpson2025ureacycledisorders pages 4-6)

3.4 Cell types primarily affected - Hepatocyte (urea-cycle compartment; site of CPS1 function). (erdal2025aminoacidmetabolism pages 10-12) - Astrocyte (brain ammonia detoxification to glutamine; cell swelling in hyperammonemia). (shakerdi2023druginducedhyperammonaemia pages 1-2, simpson2025ureacycledisordersa pages 1-4)

3.5 Anatomical locations - Liver (mitochondrial ureagenesis). (erdal2025aminoacidmetabolism pages 10-12) - Brain (encephalopathy, cerebral edema, seizures; white matter lesions reported in late-onset CPS1D). (wang2023clinicalandgenetic pages 3-5, noori2024carbamolyphosphatesynthetase1 pages 1-2)

  1. Biological processes (GO-style disrupted processes; labels) The evidence supports disruption of the following biological processes:
  2. Urea cycle / ureagenesis (impaired nitrogen excretion as urea) (bakshi2025ahypomorphicmodel pages 1-3, erdal2025aminoacidmetabolism pages 10-12)
  3. Ammonia detoxification / ammonia assimilation (failure → hyperammonemia) (noori2024carbamolyphosphatesynthetase1 pages 1-2)
  4. Amino-acid catabolic processes and nitrogen metabolism homeostasis (system-level imbalance) (noori2024carbamolyphosphatesynthetase1 pages 1-2, erdal2025aminoacidmetabolism pages 10-12)
  5. Astrocyte volume regulation / osmotic homeostasis (via glutamine accumulation) (shakerdi2023druginducedhyperammonaemia pages 1-2, simpson2025ureacycledisordersa pages 1-4)

  6. Mitochondrial function and energy metabolism (hyperammonemia may interfere with mitochondrial function) (shakerdi2023druginducedhyperammonaemia pages 1-2)

  7. Cellular components (where key processes occur)

  8. Mitochondrial matrix (CPS1 catalysis; intramitochondrial urea cycle) (yokota2025carbamoylphosphatesynthetase pages 2-3, erdal2025aminoacidmetabolism pages 10-12)
  9. Blood/plasma compartment (hyperammonemia; plasma glutamine/citrulline monitoring) (noori2024carbamolyphosphatesynthetase1 pages 2-3)

  10. Central nervous system (BBB crossing; astrocyte glutamine accumulation, cerebral edema) (shakerdi2023druginducedhyperammonaemia pages 1-2, simpson2025ureacycledisordersa pages 1-4)

  11. Disease progression: stages, triggers, and clinical phenotypes

6.1 Triggers and decompensation physiology Decompensations are often precipitated by catabolic stressors (infection, dehydration, inflammation, postpartum period, corticosteroids), increasing endogenous protein catabolism and ammonia generation. A late-onset CPS1D report lists triggers including “fever, dehydration, diarrhea … and acute upper respiratory tract inflammation.” (yokota2025carbamoylphosphatesynthetase pages 2-3)

6.2 Acute neurologic injury thresholds and reversible/irreversible phases - A clinically relevant threshold described in an adult CPS1D case report is that “cerebral edema can develop due to hyperammonemia when levels exceed 340 μg/dL (200 μM).” (yokota2025carbamoylphosphatesynthetase pages 2-3) - Rapid ammonia reduction can improve consciousness and prevent progression; the same case reports rapid improvement after extracorporeal clearance (“plasma ammonia levels decreased rapidly, and her level of consciousness quickly improved”). (yokota2025carbamoylphosphatesynthetase pages 2-3) - However, multiple sources emphasize that definitive metabolic correction (e.g., liver transplant) does not reverse established neurodevelopmental injury. (noori2024carbamolyphosphatesynthetase1 pages 2-3, vega2023ureacycledisorders pages 1-2)

6.3 Key clinical phenotypes and mechanistic links (HP-style labels) - Hyperammonemia → encephalopathy/lethargy/coma and cerebral edema (mechanistically linked to astrocyte swelling) (noori2024carbamolyphosphatesynthetase1 pages 1-2, shakerdi2023druginducedhyperammonaemia pages 1-2) - Seizures (can occur during glutamine rise; may persist even after ammonia normalization) (simpson2025ureacycledisordersa pages 1-4, simpson2025ureacycledisorders pages 4-6) - Developmental delay / neurocognitive impairment (associated with peak ammonia and recurrence frequency) (vega2023ureacycledisorders pages 1-2, martinhernandez2025understandingthenatural pages 13-15) - Vomiting, poor feeding, hypotonia in infants; neuropsychiatric symptoms in late-onset cases (dong2024clinicalfeaturesand pages 1-2, simpson2025ureacycledisordersa pages 1-4)

  1. Recent developments and latest research (priority 2023–2024)

7.1 2024 CPS1D cohort-level clinical genetics and outcomes - Dong et al. (BMC Pediatrics; publication date Aug 2024; https://doi.org/10.1186/s12887-024-05005-5) report seven Chinese patients with CPS1D (2014–2023), with peak ammonia ranging ~160 to >1000 µmol/L, and demonstrate severe neonatal mortality with survivorship after combined nitrogen-scavenger therapy and liver transplantation in one infant. (dong2024clinicalfeaturesand pages 1-2, dong2024clinicalfeaturesand pages 2-4) - Noori et al. (Molecular Genetics and Metabolism Reports; publication date Dec 2024; https://doi.org/10.1016/j.ymgmr.2024.101156) provide a tertiary-center CPS1D cohort and literature review, emphasizing rapid dialysis efficacy (example: hemodialysis lowered ammonia to 27 µmol/L within 6 h) and the canonical biomarker pattern (hyperammonemia, low citrulline, high glutamine, low urinary orotic acid). (noori2024carbamolyphosphatesynthetase1 pages 2-3)

7.2 2023–2024 therapeutics and management evidence Long-term citrulline/arginine outcomes (2023) Imbard et al. (Orphanet J Rare Dis; publication date Jul 2023; https://doi.org/10.1186/s13023-023-02800-8) report 79 UCD patients (including CPS1D cases) with median follow-up 9.5 years and biochemical outcomes during supplementation. Mean plasma ammonia during treatment was 35.9 µmol/L with citrulline, 49.8 µmol/L with arginine, and 53.0 µmol/L with combination therapy; behavior was “normal or adapted” in 98.7%, and 79.0% had “normal social life.” (imbard2023citrullineinthe pages 1-2)

Therapeutic drug monitoring for phenylbutyrate (2023) Glinton et al. (Molecular Genetics and Metabolism; publication date Nov 2023; https://doi.org/10.1016/j.ymgme.2023.107699) highlight increasing adoption of phenylbutyrate-metabolite monitoring, reporting 1,255 measurements from 387 individuals and that elevated PAA or PAA:PAGN occurred in ~4.2–4.3% of samples. They note potential toxicity signals, citing that “previous studies have suggested that plasma PAA concentrations above 500 μg/mL are toxic.” (glinton2023monitoringthetreatment pages 1-2)

Transplant decision pathways and outcomes (2023) Vega et al. (Frontiers in Pediatrics; publication date Mar 2023; https://doi.org/10.3389/fped.2023.1103757) report a real-world transplant cohort (n=33 UCD; includes CPS1D n=4). Neonatal-onset cases had mean peak ammonia 1,152 µmol/L; among those surviving the neonatal period, 59% underwent liver transplantation with 100% survival, normalized protein tolerance, but neurologic sequelae in 69% (without progression). (vega2023ureacycledisorders pages 1-2)

Visual evidence: Vega et al. provide a flowchart summarizing the clinical pathway and transplant decision-making in UCDs, useful for implementation-focused knowledge base entries. (vega2023ureacycledisorders media 5c1a54bf)

  1. Current applications and real-world implementations

8.1 Diagnostic implementation - Biochemical screening in suspected CPS1D commonly uses plasma amino acids (low citrulline; elevated glutamine/alanine) and urine organic acids (low/absent orotic acid) along with plasma ammonia measurement. (wang2023clinicalandgenetic pages 3-5, dong2024clinicalfeaturesand pages 1-2) - Increasingly, diagnosis is confirmed by genetic testing (e.g., compound heterozygous CPS1 variants reported in 2023–2024 cohorts). (wang2023clinicalandgenetic pages 3-5, dong2024clinicalfeaturesand pages 1-2)

8.2 Acute crisis management (implementation elements) Across contemporary cohort/case evidence and practice-oriented reviews: - Immediate prevention of catabolism (high-calorie infusion; protein stop/limit). - Nitrogen scavengers (benzoate, phenylacetate/phenylbutyrate). - Urea-cycle intermediate supplementation (arginine and/or citrulline depending on defect). - Rapid extracorporeal ammonia removal when severe (hemodialysis/continuous modalities). Examples: - Noori et al. cite hemodialysis lowering ammonia to 27 µmol/L within 6 h in CPS1D. (noori2024carbamolyphosphatesynthetase1 pages 2-3) - An adult CPS1D case used sodium phenylbutyrate 4500 mg/day, L-arginine 12,000 mg/day, protein restriction, and continuous hemodiafiltration (CHDF), with rapid clinical improvement. (yokota2025carbamoylphosphatesynthetase pages 2-3)

8.3 Chronic management (implementation elements) Core chronic care integrates: - Protein-restricted diet with adequate calories and essential amino acids - Nitrogen scavengers - Citrulline/arginine supplementation - Monitoring of ammonia and amino acids (especially glutamine) - Structured emergency protocols The Spanish registry reports that among medically managed UCD patients, 92% followed protein restriction and 76.2% received citrulline and/or arginine; mean doses were arginine 148 ± 113 mg/kg/day and citrulline 159 ± 83 mg/kg/day. (martinhernandez2025understandingthenatural pages 10-12)

A drug-label–level implementation reference for sodium phenylbutyrate (PHEBURANE; revised 6/2022; FDA label) provides dosing and monitoring language relevant to chronic proximal UCD care: it recommends 450–600 mg/kg/day (<20 kg) or 9.9–13 g/m2/day (≥20 kg), and states: “Monitor plasma ammonia levels to determine the need for dosage adjustment” and “Adjust the … dosage to maintain the plasma ammonia level within the normal range for the patient’s age.” (burlina2023longtermmanagementof pages 1-2, burlina2023longtermmanagementof pages 2-5)

  1. Expert opinions and authoritative analysis (evidence-based synthesis)

9.1 Determinants of outcome emphasized by experts Multiple sources converge on peak ammonia, duration of coma, and recurrence frequency as major determinants of neurodevelopmental outcome. The Spanish registry analysis notes that ammonia levels above ~300–360 µmol/L are associated with impaired neurodevelopment and that 75% of patients without neurologic impairment had ammonia <316 µmol/L, supporting aggressive early ammonia control. (martinhernandez2025understandingthenatural pages 13-15)

9.2 Transplant as definitive metabolic therapy, but limited neuro-reversal Evidence supports liver transplantation as definitive metabolic correction for CPS1D, with high survival but substantial pre-existing neurologic sequelae: - “Liver transplantation is the definitive and recommended treatment for CPS1 deficiency” (adult case report), with resolution of hyperammonemia after transplant. (yokota2025carbamoylphosphatesynthetase pages 2-3) - Vega et al. report 100% post-transplant survival in transplanted survivors, with neurologic sequelae in 69% but no progression after transplant. (vega2023ureacycledisorders pages 1-2)

  1. Relevant statistics and recent quantitative data

10.1 Hyperammonemia severity - Vega et al. (2023) neonatal-onset UCD: mean peak ammonia 1,152 µmol/L. (vega2023ureacycledisorders pages 1-2) - Dong et al. (2024) CPS1D: peak ammonia values across cases include 160, 168, 489, 514, 574, 600, >1000 µmol/L. (dong2024clinicalfeaturesand pages 2-4)

10.2 Mortality and neurologic impairment Registry-scale data (Spain; includes CPS1D) - Overall UCD mortality 14.9%; CPS1D mortality 36.8%. (martinhernandez2025understandingthenatural pages 2-3, martinhernandez2025understandingthenatural pages 5-6) - Neurological impairment occurred in 44% overall; in one excerpted table, CPS1D neurologic impairment was 7/12 (58.3%). (martinhernandez2025understandingthenatural pages 2-3, martinhernandez2025understandingthenatural pages 9-10)

Transplant outcomes - Spanish registry: transplanted patients 95.2% survival (cohort-wide). (martinhernandez2025understandingthenatural pages 2-3) - Vega et al. cohort: 100% survival among transplanted survivors, with 59% of non-neonatal-death survivors transplanted. (vega2023ureacycledisorders pages 1-2)

10.3 Long-term biochemical control and functional outcomes with citrulline/arginine - Imbard et al. (2023): mean ammonia 35.9 µmol/L with citrulline vs 49.8 µmol/L with arginine; median follow-up 9.5 years; 98.7% “normal or adapted behavior,” 79.0% “normal social life.” (imbard2023citrullineinthe pages 1-2)

10.4 Treatment monitoring adoption and safety signals - Glinton et al. (2023): 1,255 phenylbutyrate metabolite measurements from 387 individuals; elevated PAA and/or PAA:PAGN in ~4.15–4.30% of samples. (glinton2023monitoringthetreatment pages 1-2)

  1. Knowledge-base-ready structured annotations (ontology-oriented, label-level)

11.1 Pathophysiology description (concise) CPS1 deficiency is an autosomal recessive hepatic mitochondrial ureagenesis disorder in which loss of CPS1 activity at the urea-cycle entry step prevents incorporation of free ammonia into carbamoyl phosphate, causing systemic hyperammonemia, low citrulline, and compensatory nitrogen buffering as glutamine. Ammonia crosses the blood–brain barrier and is detoxified to glutamine in astrocytes, leading to intracellular glutamine accumulation, astrocyte swelling, cerebral edema, seizures, and long-term neurocognitive injury; severity is driven by peak ammonia, duration, and recurrence of crises. (noori2024carbamolyphosphatesynthetase1 pages 1-2, shakerdi2023druginducedhyperammonaemia pages 1-2, simpson2025ureacycledisordersa pages 1-4)

11.2 Gene/protein annotations - CPS1 (HGNC symbol: CPS1): mitochondrial urea-cycle enzyme; loss causes CPS1D. (dong2024clinicalfeaturesand pages 1-2) - NAGS: produces NAG, the essential CPS1 activator; mechanistically linked and key differential/phenocopy. (shakerdi2023druginducedhyperammonaemia pages 1-2, erdal2025aminoacidmetabolism pages 10-12)

11.3 Biological processes (GO-style labels) - Urea cycle / ureagenesis (bakshi2025ahypomorphicmodel pages 1-3, erdal2025aminoacidmetabolism pages 10-12) - Ammonia detoxification and nitrogen homeostasis (noori2024carbamolyphosphatesynthetase1 pages 1-2) - Astrocyte osmotic homeostasis / cerebral edema pathogenesis (shakerdi2023druginducedhyperammonaemia pages 1-2, simpson2025ureacycledisordersa pages 1-4)

11.4 Cellular components - Mitochondrial matrix (hepatic; CPS1 catalysis) (yokota2025carbamoylphosphatesynthetase pages 2-3, erdal2025aminoacidmetabolism pages 10-12) - Brain/astrocyte compartment (glutamine accumulation, swelling) (shakerdi2023druginducedhyperammonaemia pages 1-2)

11.5 Phenotype associations (HP-style labels) - Hyperammonemia; encephalopathy; cerebral edema; seizures; developmental delay; psychiatric symptoms (noori2024carbamolyphosphatesynthetase1 pages 1-2, simpson2025ureacycledisordersa pages 1-4, dong2024clinicalfeaturesand pages 1-2)

11.6 Cell type involvement (CL-style labels) - Hepatocyte (primary metabolic defect) (erdal2025aminoacidmetabolism pages 10-12) - Astrocyte (brain injury mediator) (shakerdi2023druginducedhyperammonaemia pages 1-2)

11.7 Anatomical locations (UBERON-style labels) - Liver; brain (erdal2025aminoacidmetabolism pages 10-12, wang2023clinicalandgenetic pages 3-5)

11.8 Chemical entities (ChEBI-style labels) - Ammonia, glutamine, citrulline, orotic acid, N-acetylglutamate (NAG) - Sodium phenylbutyrate / glycerol phenylbutyrate / sodium benzoate / sodium phenylacetate - N-carbamyl-L-glutamate (carglumic acid) (noori2024carbamolyphosphatesynthetase1 pages 2-3, glinton2023monitoringthetreatment pages 1-2, simpson2025ureacycledisorders pages 4-6)

  1. Evidence items with publication dates and URLs (PMID note) PMIDs were not available in the extracted tool context for the papers below; DOIs/URLs and publication months/years are provided.

Key 2023–2024 CPS1D-focused sources - Vega et al. “Urea cycle disorders and indications for liver transplantation.” Frontiers in Pediatrics. Mar 2023. https://doi.org/10.3389/fped.2023.1103757 (vega2023ureacycledisorders pages 1-2, vega2023ureacycledisorders media 5c1a54bf) - Wang et al. “Clinical and genetic analysis of a case of late onset carbamoyl phosphate synthase I deficiency…” BMC Medical Genomics. Jun 2023. https://doi.org/10.1186/s12920-023-01569-w (wang2023clinicalandgenetic pages 3-5) - Imbard et al. “Citrulline in the management of patients with urea cycle disorders.” Orphanet J Rare Dis. Jul 2023. https://doi.org/10.1186/s13023-023-02800-8 (imbard2023citrullineinthe pages 1-2, imbard2023citrullineinthe pages 2-4) - Glinton et al. “Monitoring the treatment of urea cycle disorders using phenylbutyrate metabolite analyses…” Mol Genet Metab. Nov 2023. https://doi.org/10.1016/j.ymgme.2023.107699 (glinton2023monitoringthetreatment pages 1-2) - Shakerdi & Ryan. “Drug-induced hyperammonaemia.” J Clin Pathol. May 2023. https://doi.org/10.1136/jcp-2022-208644 (shakerdi2023druginducedhyperammonaemia pages 1-2) - Dong et al. “Clinical features and CPS1 variants in Chinese patients with carbamoyl phosphate synthetase 1 deficiency.” BMC Pediatrics. Aug 2024. https://doi.org/10.1186/s12887-024-05005-5 (dong2024clinicalfeaturesand pages 1-2, dong2024clinicalfeaturesand pages 2-4) - Noori et al. “Carbamoly-phosphate synthetase 1 (CPS1) deficiency: a tertiary center retrospective cohort study and literature review.” Mol Genet Metab Rep. Dec 2024. https://doi.org/10.1016/j.ymgmr.2024.101156 (noori2024carbamolyphosphatesynthetase1 pages 2-3)

Additional authoritative implementation reference - FDA label: PHEBURANE (sodium phenylbutyrate) oral pellets. Revised 6/2022. https://www.fda.gov/drugsatfda (burlina2023longtermmanagementof pages 1-2, burlina2023longtermmanagementof pages 2-5)

Limitations of this report - MONDO ID and many explicit ontology numeric identifiers (GO/HP/CL/UBERON/ChEBI) were not retrieved from the tool context; the report provides ontology-aligned labels suitable for curation but not authoritative ID mapping. - PMIDs were not provided in the retrieved evidence. Where PMID is required for a database entry, the DOI/URL can be used to retrieve the PubMed record.

References

  1. (noori2024carbamolyphosphatesynthetase1 pages 2-3): Mahmood Noori, Omar Jarrah, and Aisha Al Shamsi. Carbamoly-phosphate synthetase 1 (cps1) deficiency: a tertiary center retrospective cohort study and literature review. Dec 2024. URL: https://doi.org/10.1016/j.ymgmr.2024.101156, doi:10.1016/j.ymgmr.2024.101156. This article has 2 citations.

  2. (noori2024carbamolyphosphatesynthetase1 pages 1-2): Mahmood Noori, Omar Jarrah, and Aisha Al Shamsi. Carbamoly-phosphate synthetase 1 (cps1) deficiency: a tertiary center retrospective cohort study and literature review. Dec 2024. URL: https://doi.org/10.1016/j.ymgmr.2024.101156, doi:10.1016/j.ymgmr.2024.101156. This article has 2 citations.

  3. (dong2024clinicalfeaturesand pages 1-2): Hui Dong, Tian Sang, Xue Ma, Jinqing Song, Zhehui Chen, Huiting Zhang, Ying Jin, Mengqiu Li, Dingding Dong, Liying Sun, Zhijun Zhu, Yao Zhang, and Yanling Yang. Clinical features and cps1 variants in chinese patients with carbamoyl phosphate synthetase 1 deficiency. BMC Pediatrics, Aug 2024. URL: https://doi.org/10.1186/s12887-024-05005-5, doi:10.1186/s12887-024-05005-5. This article has 1 citations and is from a peer-reviewed journal.

  4. (erdal2025aminoacidmetabolism pages 10-12): Ranya Erdal, Kıvanç Birsoy, and Gokhan Unlu. Amino acid metabolism in liver mitochondria: from homeostasis to disease. Metabolites, 15:446, Jul 2025. URL: https://doi.org/10.3390/metabo15070446, doi:10.3390/metabo15070446. This article has 2 citations.

  5. (shakerdi2023druginducedhyperammonaemia pages 1-2): Loai Shakerdi and Aidan Ryan. Drug-induced hyperammonaemia. Journal of Clinical Pathology, 76:501-509, May 2023. URL: https://doi.org/10.1136/jcp-2022-208644, doi:10.1136/jcp-2022-208644. This article has 25 citations and is from a peer-reviewed journal.

  6. (yokota2025carbamoylphosphatesynthetase pages 2-3): Kazuhiro Yokota, Akira Ohtake, Taro Yamazaki, Takuma Tsuzuki-Wada, Megumi Saito-Tsuruoka, Takuya Fushimi, Kei Murayama, Yuji Akiyama, and Toshihide Mimura. Carbamoyl phosphate synthetase 1 deficiency manifested in an adult treated with prednisone for polymyositis, and cured by live-donor liver transplantation. Jun 2025. URL: https://doi.org/10.1016/j.ymgmr.2025.101200, doi:10.1016/j.ymgmr.2025.101200. This article has 1 citations.

  7. (wang2023clinicalandgenetic pages 3-5): Shangyu Wang, Jinglin Chen, Xiaoqi Zhu, Tingting Huang, Haifeng Xu, Guohuan Ying, Hao Qian, Wenxin Lin, Yiehen Tung, Kaleem Ullah Khan, Hu Guo, Guo Zheng, Haiying Lu, and Gang Zhang. Clinical and genetic analysis of a case of late onset carbamoyl phosphate synthase i deficiency caused by cps1 mutation and literature review. BMC Medical Genomics, Jun 2023. URL: https://doi.org/10.1186/s12920-023-01569-w, doi:10.1186/s12920-023-01569-w. This article has 5 citations and is from a peer-reviewed journal.

  8. (simpson2025ureacycledisordersa pages 1-4): KL Simpson, EL MacLeod, and A Kakajiwala. Urea cycle disorders overview. Unknown journal, 2025.

  9. (imbard2023citrullineinthe pages 1-2): Apolline Imbard, Juliette Bouchereau, Jean-Baptiste Arnoux, Anaïs Brassier, Manuel Schiff, Claire-Marine Bérat, Clément Pontoizeau, Jean-François Benoist, Constant Josse, François Montestruc, and Pascale de Lonlay. Citrulline in the management of patients with urea cycle disorders. Orphanet Journal of Rare Diseases, Jul 2023. URL: https://doi.org/10.1186/s13023-023-02800-8, doi:10.1186/s13023-023-02800-8. This article has 14 citations and is from a peer-reviewed journal.

  10. (glinton2023monitoringthetreatment pages 1-2): Kevin E. Glinton, Charles G. Minard, Ning Liu, Qin Sun, Sarah H. Elsea, Lindsay C. Burrage, and Sandesh C.S. Nagamani. Monitoring the treatment of urea cycle disorders using phenylbutyrate metabolite analyses: still many lessons to learn. Molecular Genetics and Metabolism, 140:107699, Nov 2023. URL: https://doi.org/10.1016/j.ymgme.2023.107699, doi:10.1016/j.ymgme.2023.107699. This article has 3 citations and is from a peer-reviewed journal.

  11. (simpson2025ureacycledisorders pages 4-6): KL Simpson, EL MacLeod, and A Kakajiwala. Urea cycle disorders overview. Unknown journal, 2025.

  12. (bakshi2025ahypomorphicmodel pages 1-3): Stuti Bakshi, Taryn Diep, Brandon J. Willis, Rachel Reyes, Grace F. Wu, Georgios Makris, Martin Poms, Isabel Day, Qin Sun, Irina Zhuravka, Lindsay Lueptow, Michelle Tang, Gareth A. Cromie, Aimée M. Dudley, Johannes Häberle, and Gerald S. Lipshutz. A hypomorphic model of cps1 deficiency for investigating the effects of hyperammonemia on the developing nervous system. Disease Models & Mechanisms, Jun 2025. URL: https://doi.org/10.1242/dmm.052303, doi:10.1242/dmm.052303. This article has 0 citations and is from a domain leading peer-reviewed journal.

  13. (vega2023ureacycledisorders pages 1-2): Marta García Vega, José D. Andrade, Ana Morais, Esteban Frauca, Gema Muñoz Bartolo, María D. Lledín, Ana Bergua, and Loreto Hierro. Urea cycle disorders and indications for liver transplantation. Frontiers in Pediatrics, Mar 2023. URL: https://doi.org/10.3389/fped.2023.1103757, doi:10.3389/fped.2023.1103757. This article has 16 citations.

  14. (martinhernandez2025understandingthenatural pages 13-15): Elena Martín-Hernández, Marcello Bellusci, Patricia Pérez-Mohand, Patricia Correcher Medina, Javier Blasco-Alonso, Ana Morais-López, Javier de las Heras, Silvia María Meavilla Olivas, Lucy Dougherty-de Miguel, Maria Luz Couce, Elvira Cañedo Villarroya, María Concepción García Jiménez, Pedro Juan Moreno-Lozano, Inmaculada Vives, Mercedes Gil-Campos, Sinziana Stanescu, Leticia Ceberio-Hualde, María Camprodón, Elisenda Cortès-Saladelafont, Rafael López-Urdiales, Mercedes Murray Hurtado, Ana María Márquez Armenteros, Concha Sierra Córcoles, Luis Peña-Quintana, Mónica Ruiz-Pons, Carlos Alcalde, Fernando Castellanos-Pinedo, Elena Dios, Delia Barrio-Carreras, María Martín-Cazaña, Mónica García-Peris, José David Andrade, Camila García-Volpe, Mariela de los Santos, Angels García-Cazorla, Mireia del Toro, Ana Felipe-Rucián, María José Comino Monroy, Paula Sánchez-Pintos, Ana Matas, David Gil Ortega, Álvaro Martín-Rivada, Ana Bergua, Amaya Belanger-Quintana, Isidro Vitoria, Raquel Yahyaoui, Belén Pérez, Montserrat Morales-Conejo, and Pilar Quijada-Fraile. Understanding the natural history and the effects of current therapeutic strategies on urea cycle disorders: insights from the ucd spanish registry. Nutrients, 17:1173, Mar 2025. URL: https://doi.org/10.3390/nu17071173, doi:10.3390/nu17071173. This article has 0 citations.

  15. (dong2024clinicalfeaturesand pages 2-4): Hui Dong, Tian Sang, Xue Ma, Jinqing Song, Zhehui Chen, Huiting Zhang, Ying Jin, Mengqiu Li, Dingding Dong, Liying Sun, Zhijun Zhu, Yao Zhang, and Yanling Yang. Clinical features and cps1 variants in chinese patients with carbamoyl phosphate synthetase 1 deficiency. BMC Pediatrics, Aug 2024. URL: https://doi.org/10.1186/s12887-024-05005-5, doi:10.1186/s12887-024-05005-5. This article has 1 citations and is from a peer-reviewed journal.

  16. (vega2023ureacycledisorders media 5c1a54bf): Marta García Vega, José D. Andrade, Ana Morais, Esteban Frauca, Gema Muñoz Bartolo, María D. Lledín, Ana Bergua, and Loreto Hierro. Urea cycle disorders and indications for liver transplantation. Frontiers in Pediatrics, Mar 2023. URL: https://doi.org/10.3389/fped.2023.1103757, doi:10.3389/fped.2023.1103757. This article has 16 citations.

  17. (martinhernandez2025understandingthenatural pages 10-12): Elena Martín-Hernández, Marcello Bellusci, Patricia Pérez-Mohand, Patricia Correcher Medina, Javier Blasco-Alonso, Ana Morais-López, Javier de las Heras, Silvia María Meavilla Olivas, Lucy Dougherty-de Miguel, Maria Luz Couce, Elvira Cañedo Villarroya, María Concepción García Jiménez, Pedro Juan Moreno-Lozano, Inmaculada Vives, Mercedes Gil-Campos, Sinziana Stanescu, Leticia Ceberio-Hualde, María Camprodón, Elisenda Cortès-Saladelafont, Rafael López-Urdiales, Mercedes Murray Hurtado, Ana María Márquez Armenteros, Concha Sierra Córcoles, Luis Peña-Quintana, Mónica Ruiz-Pons, Carlos Alcalde, Fernando Castellanos-Pinedo, Elena Dios, Delia Barrio-Carreras, María Martín-Cazaña, Mónica García-Peris, José David Andrade, Camila García-Volpe, Mariela de los Santos, Angels García-Cazorla, Mireia del Toro, Ana Felipe-Rucián, María José Comino Monroy, Paula Sánchez-Pintos, Ana Matas, David Gil Ortega, Álvaro Martín-Rivada, Ana Bergua, Amaya Belanger-Quintana, Isidro Vitoria, Raquel Yahyaoui, Belén Pérez, Montserrat Morales-Conejo, and Pilar Quijada-Fraile. Understanding the natural history and the effects of current therapeutic strategies on urea cycle disorders: insights from the ucd spanish registry. Nutrients, 17:1173, Mar 2025. URL: https://doi.org/10.3390/nu17071173, doi:10.3390/nu17071173. This article has 0 citations.

  18. (burlina2023longtermmanagementof pages 1-2): Alberto Burlina, Serena Gasperini, Giancarlo la Marca, Andrea Pession, Barbara Siri, Marco Spada, Margherita Ruoppolo, and Albina Tummolo. Long-term management of patients with mild urea cycle disorders identified through the newborn screening: an expert opinion for clinical practice. Nutrients, 16:13, Dec 2023. URL: https://doi.org/10.3390/nu16010013, doi:10.3390/nu16010013. This article has 10 citations.

  19. (burlina2023longtermmanagementof pages 2-5): Alberto Burlina, Serena Gasperini, Giancarlo la Marca, Andrea Pession, Barbara Siri, Marco Spada, Margherita Ruoppolo, and Albina Tummolo. Long-term management of patients with mild urea cycle disorders identified through the newborn screening: an expert opinion for clinical practice. Nutrients, 16:13, Dec 2023. URL: https://doi.org/10.3390/nu16010013, doi:10.3390/nu16010013. This article has 10 citations.

  20. (martinhernandez2025understandingthenatural pages 2-3): Elena Martín-Hernández, Marcello Bellusci, Patricia Pérez-Mohand, Patricia Correcher Medina, Javier Blasco-Alonso, Ana Morais-López, Javier de las Heras, Silvia María Meavilla Olivas, Lucy Dougherty-de Miguel, Maria Luz Couce, Elvira Cañedo Villarroya, María Concepción García Jiménez, Pedro Juan Moreno-Lozano, Inmaculada Vives, Mercedes Gil-Campos, Sinziana Stanescu, Leticia Ceberio-Hualde, María Camprodón, Elisenda Cortès-Saladelafont, Rafael López-Urdiales, Mercedes Murray Hurtado, Ana María Márquez Armenteros, Concha Sierra Córcoles, Luis Peña-Quintana, Mónica Ruiz-Pons, Carlos Alcalde, Fernando Castellanos-Pinedo, Elena Dios, Delia Barrio-Carreras, María Martín-Cazaña, Mónica García-Peris, José David Andrade, Camila García-Volpe, Mariela de los Santos, Angels García-Cazorla, Mireia del Toro, Ana Felipe-Rucián, María José Comino Monroy, Paula Sánchez-Pintos, Ana Matas, David Gil Ortega, Álvaro Martín-Rivada, Ana Bergua, Amaya Belanger-Quintana, Isidro Vitoria, Raquel Yahyaoui, Belén Pérez, Montserrat Morales-Conejo, and Pilar Quijada-Fraile. Understanding the natural history and the effects of current therapeutic strategies on urea cycle disorders: insights from the ucd spanish registry. Nutrients, 17:1173, Mar 2025. URL: https://doi.org/10.3390/nu17071173, doi:10.3390/nu17071173. This article has 0 citations.

  21. (martinhernandez2025understandingthenatural pages 5-6): Elena Martín-Hernández, Marcello Bellusci, Patricia Pérez-Mohand, Patricia Correcher Medina, Javier Blasco-Alonso, Ana Morais-López, Javier de las Heras, Silvia María Meavilla Olivas, Lucy Dougherty-de Miguel, Maria Luz Couce, Elvira Cañedo Villarroya, María Concepción García Jiménez, Pedro Juan Moreno-Lozano, Inmaculada Vives, Mercedes Gil-Campos, Sinziana Stanescu, Leticia Ceberio-Hualde, María Camprodón, Elisenda Cortès-Saladelafont, Rafael López-Urdiales, Mercedes Murray Hurtado, Ana María Márquez Armenteros, Concha Sierra Córcoles, Luis Peña-Quintana, Mónica Ruiz-Pons, Carlos Alcalde, Fernando Castellanos-Pinedo, Elena Dios, Delia Barrio-Carreras, María Martín-Cazaña, Mónica García-Peris, José David Andrade, Camila García-Volpe, Mariela de los Santos, Angels García-Cazorla, Mireia del Toro, Ana Felipe-Rucián, María José Comino Monroy, Paula Sánchez-Pintos, Ana Matas, David Gil Ortega, Álvaro Martín-Rivada, Ana Bergua, Amaya Belanger-Quintana, Isidro Vitoria, Raquel Yahyaoui, Belén Pérez, Montserrat Morales-Conejo, and Pilar Quijada-Fraile. Understanding the natural history and the effects of current therapeutic strategies on urea cycle disorders: insights from the ucd spanish registry. Nutrients, 17:1173, Mar 2025. URL: https://doi.org/10.3390/nu17071173, doi:10.3390/nu17071173. This article has 0 citations.

  22. (martinhernandez2025understandingthenatural pages 9-10): Elena Martín-Hernández, Marcello Bellusci, Patricia Pérez-Mohand, Patricia Correcher Medina, Javier Blasco-Alonso, Ana Morais-López, Javier de las Heras, Silvia María Meavilla Olivas, Lucy Dougherty-de Miguel, Maria Luz Couce, Elvira Cañedo Villarroya, María Concepción García Jiménez, Pedro Juan Moreno-Lozano, Inmaculada Vives, Mercedes Gil-Campos, Sinziana Stanescu, Leticia Ceberio-Hualde, María Camprodón, Elisenda Cortès-Saladelafont, Rafael López-Urdiales, Mercedes Murray Hurtado, Ana María Márquez Armenteros, Concha Sierra Córcoles, Luis Peña-Quintana, Mónica Ruiz-Pons, Carlos Alcalde, Fernando Castellanos-Pinedo, Elena Dios, Delia Barrio-Carreras, María Martín-Cazaña, Mónica García-Peris, José David Andrade, Camila García-Volpe, Mariela de los Santos, Angels García-Cazorla, Mireia del Toro, Ana Felipe-Rucián, María José Comino Monroy, Paula Sánchez-Pintos, Ana Matas, David Gil Ortega, Álvaro Martín-Rivada, Ana Bergua, Amaya Belanger-Quintana, Isidro Vitoria, Raquel Yahyaoui, Belén Pérez, Montserrat Morales-Conejo, and Pilar Quijada-Fraile. Understanding the natural history and the effects of current therapeutic strategies on urea cycle disorders: insights from the ucd spanish registry. Nutrients, 17:1173, Mar 2025. URL: https://doi.org/10.3390/nu17071173, doi:10.3390/nu17071173. This article has 0 citations.

  23. (imbard2023citrullineinthe pages 2-4): Apolline Imbard, Juliette Bouchereau, Jean-Baptiste Arnoux, Anaïs Brassier, Manuel Schiff, Claire-Marine Bérat, Clément Pontoizeau, Jean-François Benoist, Constant Josse, François Montestruc, and Pascale de Lonlay. Citrulline in the management of patients with urea cycle disorders. Orphanet Journal of Rare Diseases, Jul 2023. URL: https://doi.org/10.1186/s13023-023-02800-8, doi:10.1186/s13023-023-02800-8. This article has 14 citations and is from a peer-reviewed journal.