⚙

Pathophysiology

4

CPS1 molecular function deficiency

Biallelic pathogenic variants in CPS1 reduce mitochondrial carbamoyl phosphate synthetase catalytic activity.

hepatocyte link

CPS1 link

carbamoyl phosphate biosynthetic process link ↓ DECREASED

carbamoyl-phosphate synthase (ammonia) activity link ↓ DECREASED

mitochondrion link

Downstream

Impaired mitochondrial ureagenesis Reduced CPS1 activity blocks carbamoyl phosphate generation and proximal urea-cycle flux.

Show evidence (1 reference)

PMID:39469307 SUPPORT Human Clinical

"CPS1 is an enzyme in the urea cycle that catalyzes ammonia and bicarbonate condensation."

Supports CPS1 catalytic dysfunction as the initiating molecular event.

Impaired mitochondrial ureagenesis

Reduced CPS1 function in hepatic mitochondria impairs ATP-dependent condensation of ammonia and bicarbonate into carbamoyl phosphate, the first and rate-limiting step of the urea cycle. This blocks hepatic nitrogen disposal and causes systemic ammonia accumulation. The reaction is functionally dependent on N-acetylglutamate (NAG) as an essential allosteric activator.

urea cycle link

liver link

Downstream

Plasma ammonia Failed CPS1-dependent ureagenesis prevents ammonia disposal and elevates circulating ammonia.

Plasma citrulline Proximal urea-cycle block reduces carbamoyl phosphate entry into downstream citrulline synthesis.

Urinary orotic acid Proximal carbamoyl phosphate deficiency limits overflow into pyrimidine synthesis, leaving urinary orotic acid normal or low rather than elevated.

Hyperammonemia Ammonia accumulation from impaired ureagenesis manifests as hyperammonemia.

Hyperammonemia-driven neurotoxicity Systemic ammonia accumulation exposes the brain to ammonia neurotoxicity.

Compensatory nitrogen buffering as glutamine Nitrogen that cannot be cleared as urea is buffered in amino acids, especially glutamine.

Show evidence (2 references)

PMID:39469307 SUPPORT Human Clinical

"CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive."

Supports severe hyperammonemic consequences downstream of impaired proximal ureagenesis.

PMID:40710547 SUPPORT Other

"Hepatic mitochondria play critical roles in sustaining systemic nutrient balance, nitrogen detoxification, and cellular bioenergetics."

Review supporting the role of hepatic mitochondria in nitrogen detoxification via the urea cycle.

Hyperammonemia-driven neurotoxicity

Failure of hepatic ureagenesis causes systemic hyperammonemia. Ammonia is specifically neurotoxic and readily crosses the blood-brain barrier. In astrocytes, ammonia is detoxified to glutamine via glutamine synthetase, leading to excessive intracellular glutamine accumulation. This causes osmotic astrocyte swelling, cerebral edema, raised intracranial pressure, and encephalopathy. Hyperammonemia may also interfere with mitochondrial function and neurotransmission.

astrocyte link

glutamine biosynthetic process link cellular response to nitrogen compound link cellular response to osmotic stress link

brain link

Downstream

Encephalopathy Hyperammonemia produces acute neurologic dysfunction that can progress from confusion to unconsciousness.

Cerebral edema Severe ammonia neurotoxicity can produce cerebral edema through osmotic astrocyte injury.

Coma Severe hyperammonemic encephalopathy can progress to coma.

Seizures Hyperammonemic decompensation can provoke seizures during acute neonatal or late-onset crises.

Lethargy Neonatal hyperammonemic illness often begins with reduced alertness before progressing to coma.

Hypotonia Hyperammonemic metabolic crises can manifest with reduced muscle tone as part of acute neonatal neurologic decompensation.

Vomiting Vomiting is part of the acute systemic presentation of neonatal urea-cycle decompensation.

Global developmental delay Recurrent or severe early hyperammonemia can leave permanent developmental sequelae.

Intellectual disability Long-term cognitive impairment can follow neonatal crises or present in late-onset CPS1D.

Microcephaly Early recurrent hyperammonemia can impair brain growth and lead to microcephaly.

Abnormal cerebral white matter morphology Hyperammonemic CPS1D crises can be accompanied by diffuse white matter injury on MRI.

Atypical behavior Partial CPS1D can manifest with psychiatric or behavioral symptoms during late-onset disease.

Show evidence (2 references)

PMID:39469307 PARTIAL Human Clinical

"CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive."

Supports hyperammonemia-linked neurological injury in CPS1D; cellular astrocyte swelling details are inferred from established ammonia neurotoxicity mechanisms.

PMID:33409766 SUPPORT Other

"Ammonia diffuses freely across the blood–brain barrier and is converted with alanine to glutamine by glutamine synthase. Glutamine is the main intracellular osmole of the brain. Its accumulation causes the swelling of astrocytes during hyperammonemia"

This UCD review supports the blood-brain-barrier crossing and astrocyte glutamine osmolyte mechanism.

Compensatory nitrogen buffering as glutamine

When urea synthesis is blocked, the body compensates by storing excess nitrogen as glutamine. Plasma glutamine rises as a major nitrogen carrier and serves as a clinical index of total nitrogen load.

urea cycle link

Downstream

Plasma glutamine Excess nitrogen is buffered as glutamine, elevating plasma glutamine.

Show evidence (2 references)

PMID:39469307 SUPPORT Human Clinical

"Ammonia results from amino acid turnover and is produced by intestinal urease-positive bacteria. Ammonia must be detoxified, and the urea cycle converts ammonia into urea."

Supports the role of the urea cycle in ammonia disposal and the consequence of its disruption.

PMID:40125546 SUPPORT Human Clinical

"Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels."

Confirms the characteristic biochemical pattern of low citrulline and high glutamine in CPS1D.

⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

●

Phenotypes

13

Digestive 1

Vomiting Vomiting (HP:0002013)

Vomiting is a well-recognized feature of acute hyperammonemic crises in UCDs but specific quantitative data for CPS1D from the available abstracts is limited.

Show evidence (1 reference)

PMID:27860485 SUPPORT Other

"When presenting in the neonatal period, typically after a variable symptom-free interval, UCDs are characterized by overwhelming illness that rapidly progresses from poor feeding, vomiting, lethargy and/or irritability to coma and/or death"

UCD review supports vomiting during neonatal hyperammonemic decompensation.

Head and Neck 1

Microcephaly Microcephaly (HP:0000252)

Show evidence (1 reference)

PMID:39469307 SUPPORT Human Clinical

"One patient had recurrent hyperammonemia episodes in her first year of life, which led to microcephaly and global developmental delay."

Directly documents microcephaly resulting from recurrent hyperammonemia in a CPS1D patient.

Metabolism 2

Hyperammonemia Hyperammonemia (HP:0001987)

Show evidence (2 references)

PMID:39174957 SUPPORT Human Clinical

"Peak blood ammonia levels ranged from 160 to 1,000 µmol/L."

Quantifies the range of hyperammonemia severity across a CPS1D cohort.

PMID:40218931 SUPPORT Human Clinical

"The median ammonia level in deceased patients was higher at 1058 µmol/L (IQR 410-1793) than in survivors at 294 µmol/L (IQR 71-494)"

Spanish registry data showing ammonia severity correlates with mortality.

Cerebral edema Cerebral edema (HP:0002181)

Show evidence (1 reference)

PMID:33409766 SUPPORT Other

"emergent hemodialysis is mandatory before referral to a reference center if ammonia levels are above 200 µmol/l as the risk of cerebral edema is then above 55%."

Supports cerebral edema risk when hyperammonemia is severe in urea-cycle disorders.

Musculoskeletal 1

Hypotonia Hypotonia (HP:0001252)

The disease-specific CPS1D abstracts support neonatal hyperammonemic neurologic deterioration, while the broader E-IMD OAD/UCD registry abstract provides the exact quotable support for muscular hypotonia during acute metabolic crises.

Show evidence (1 reference)

PMID:25875215 SUPPORT Human Clinical

"vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency"

Human registry data list muscular hypotonia during acute OAD/UCD metabolic crises and name carbamylphosphate 1 synthetase deficiency among disorders with frequent neonatal onset.

Nervous System 8

Encephalopathy Encephalopathy (HP:0001298)

Show evidence (2 references)

PMID:39469307 SUPPORT Human Clinical

"CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive."

Supports encephalopathy as a direct consequence of hyperammonemia in CPS1D.

PMID:40125546 SUPPORT Human Clinical

"the patient, without apparent cause, suddenly developed confusion progressing to unconsciousness and coma."

Case report demonstrating acute encephalopathy progression in adult-onset CPS1D.

Seizures Seizure (HP:0001250)

Show evidence (1 reference)

PMID:28658158 SUPPORT Human Clinical

"Then seizure and tachypnoea reappeared as intravenous amino acids were provided. Further examination indicated severe hyperammonemia (serum ammonia level >500mmol/L)."

Directly documents seizure during severe neonatal CPS1D hyperammonemia.

Coma Coma (HP:0001259)

Show evidence (1 reference)

PMID:40125546 SUPPORT Human Clinical

"the patient, without apparent cause, suddenly developed confusion progressing to unconsciousness and coma."

The adult-onset CPS1D case directly documents coma during hyperammonemic decompensation.

Global developmental delay Global developmental delay (HP:0001263)

Show evidence (2 references)

PMID:39469307 SUPPORT Human Clinical

"One patient had recurrent hyperammonemia episodes in her first year of life, which led to microcephaly and global developmental delay."

Directly documents global developmental delay resulting from recurrent hyperammonemia in CPS1D.

PMID:40218931 SUPPORT Human Clinical

"Neurological impairment occurred in 44% of patients, with worse neurological outcomes observed in patients with argininosuccinate lyase deficiency, arginase 1 deficiency, hyperornithinemia-hyperammonemia-homocitrullinuria, EO presentations, pre-2014 diagnosis, and patients with higher levels of..."

Registry data demonstrating high rates of neurological impairment in UCDs including CPS1D.

Intellectual disability Intellectual disability (HP:0001249)

Show evidence (1 reference)

PMID:39174957 SUPPORT Human Clinical

"The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets."

Directly supports intellectual disability as a presenting feature in late-onset CPS1D.

Lethargy Lethargy (HP:0001254)

Show evidence (1 reference)

PMID:27860485 SUPPORT Other

"When presenting in the neonatal period, typically after a variable symptom-free interval, UCDs are characterized by overwhelming illness that rapidly progresses from poor feeding, vomiting, lethargy and/or irritability to coma and/or death"

UCD review supports lethargy during neonatal hyperammonemic deterioration.

Abnormal cerebral white matter morphology Abnormal cerebral white matter morphology (HP:0002500)

Show evidence (1 reference)

PMID:37365635 SUPPORT Human Clinical

"MRI of the brain showed diffuse white matter lesions."

Directly documents white matter lesions on MRI in a late-onset CPS1D case.

Atypical behavior Atypical behavior (HP:0000708)

Show evidence (1 reference)

PMID:39174957 SUPPORT Human Clinical

"The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets."

Directly supports psychiatric/behavioral symptoms as a feature of late-onset CPS1D.

🧬

Genetic Associations

2

CPS1 pathogenic variants

Autosomal recessive

Show evidence (1 reference)

PMID:39174957 SUPPORT Human Clinical

"No hotspot variants were observed among the patients. Our data contribute to expanding the mutation spectrum of CPS1."

Supports extensive allelic heterogeneity without recurrent hotspot mutations in CPS1D.

CPS1 (Pathogenic Variants)

Show evidence (1 reference)

CGGV:assertion_dbc4dbbe-8827-4d68-a396-8368f3801e78-2018-10-12T160000.000Z SUPPORT Other

ClinGen classifies the CPS1-carbamoyl phosphate synthetase I deficiency disease gene-disease relationship as definitive with autosomal recessive inheritance.

💊

Treatments

7

Protein-restricted diet

Action: dietary intervention MAXO:0000088

Restriction of dietary protein intake is the cornerstone of chronic CPS1D management, aimed at reducing endogenous nitrogen load and preventing hyperammonemic crises. Adequate calories and essential amino acids must be maintained. In the Spanish UCD registry, 92% of medically managed patients followed protein restriction.

Mechanism Target:

INHIBITS Compensatory nitrogen buffering as glutamine — Protein restriction lowers dietary nitrogen load, reducing ammonia and glutamine accumulation pressure when ureagenesis is impaired.

Show evidence (1 reference)

PMID:38201843 SUPPORT Other

"The therapy should be based on a low-protein diet and nitrogen scavengers."

Expert consensus supports low-protein diet as a core UCD therapy.

Target Phenotypes: Hyperammonemia ↗ Encephalopathy ↗

Show evidence (1 reference)

PMID:38201843 SUPPORT Other

"The therapy should be based on a low-protein diet and nitrogen scavengers."

Expert consensus supporting protein-restricted diet as foundational therapy in UCDs.

Nitrogen scavenger therapy

Action: nitrogen scavenger therapy Ontology label: Pharmacotherapy NCIT:C15986

Agent: sodium phenylbutyrate ↗ glycerol phenylbutyrate ↗ sodium benzoate ↗

Sodium phenylbutyrate, glycerol phenylbutyrate, or sodium benzoate are used to provide alternative pathways for nitrogen excretion. These medications conjugate with glutamine or glycine to form renally excreted waste nitrogen compounds. Therapeutic drug monitoring of phenylbutyrate metabolites is increasingly adopted, as elevated phenylacetate concentrations above 500 ug/mL may be toxic.

Mechanism Target:

BYPASSES Impaired mitochondrial ureagenesis — Nitrogen scavengers provide alternative renal nitrogen-excretion routes that bypass the blocked urea-cycle entry step.

Show evidence (1 reference)

PMID:33409766 SUPPORT Other

"Ammonia is diverted to the glycine and hippuric acid pathway by benzoate, and to the glutamine and phenylacetylglutamine pathway allowing elimination in the urine without passing through the urea cycle"

UCD management review explains the bypass mechanism of benzoate and phenylacetate pathways.

Target Phenotypes: Hyperammonemia ↗

Show evidence (1 reference)

PMID:37717413 SUPPORT Human Clinical

"Medications that elicit an alternate pathway for nitrogen excretion such as oral sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB) and intravenous sodium phenylacetate (NaPAA) are important for the management of urea cycle disorders (UCDs)."

Directly supports nitrogen scavenger therapy as important in UCD management.

Citrulline and arginine supplementation

Action: nutritional supplementation MAXO:0000106

Agent: citrulline ↗ L-arginine ↗

Supplementation with citrulline and/or arginine provides urea cycle intermediates to maximize residual ammonia excretion capacity. In a study of 79 UCD patients including CPS1D cases, mean ammonia during citrulline treatment was 35.9 umol/L versus 49.8 umol/L with arginine alone. At last evaluation, 98.7% showed normal or adapted behavior and 79.0% had normal social life.

Mechanism Target:

MODULATES Impaired mitochondrial ureagenesis — Citrulline and/or arginine supplementation supplies downstream urea-cycle intermediates to support residual nitrogen disposal.

Show evidence (1 reference)

PMID:37480106 SUPPORT Human Clinical

"supplementation with amino acids involved in the urea cycle (arginine and/or citrulline, depending on the enzyme deficiency), to maximize ammonia excretion through the urea cycle"

UCD cohort paper supports amino-acid supplementation to maximize ammonia excretion.

Target Phenotypes: Hyperammonemia ↗

Show evidence (2 references)

PMID:37480106 SUPPORT Human Clinical

"During treatment, mean ammonia concentrations were 35.9 µmol/L with citrulline, 49.8 µmol/L with arginine, and 53.0 µmol/L with arginine + citrulline."

Quantifies ammonia control with citrulline versus arginine supplementation in UCDs.

PMID:37480106 SUPPORT Human Clinical

"At last evaluation, mean height and weight for age were normal and most patients showed normal or adapted behavior (98.7%) and normal social life (79.0%)."

Long-term functional outcomes supporting citrulline supplementation efficacy.

Carglumic acid (N-carbamylglutamate)

Action: Pharmacotherapy NCIT:C15986

Agent: carglumic acid ↗

Carglumic acid is a synthetic analog of N-acetylglutamate (NAG), the essential allosteric activator of CPS1. It can restore residual urea cycle activity in patients with some remaining CPS1 enzyme, and may normalize ammonia levels. All surviving patients in the Noori et al. cohort except one were on carglumic acid, which may have contributed to their survival and disease control.

Mechanism Target:

ACTIVATES CPS1 molecular function deficiency — Carglumic acid is an N-acetylglutamate analog that can activate residual CPS1 activity in selected patients.

Show evidence (1 reference)

PMID:33409766 SUPPORT Other

"It works by replacing NAG which is an essential activator of CPS1"

UCD review supports the NAG-analog mechanism for carglumic acid acting through CPS1 activation.

Target Phenotypes: Hyperammonemia ↗

Show evidence (2 references)

PMID:33409766 SUPPORT Other

"It works by replacing NAG which is an essential activator of CPS1"

Supports carglumic acid as a NAG analog that activates CPS1-dependent urea-cycle function.

PMID:39469307 SUPPORT Human Clinical

"All patients except one were on Carglumic acid which could contribute to their survival and disease control."

Directly supports carglumic acid use and its potential contribution to survival in CPS1D.

Acute crisis management with dialysis

Action: supportive care MAXO:0000950

During severe hyperammonemic crises, rapid extracorporeal ammonia removal by hemodialysis or continuous hemodiafiltration is essential. Noori et al. report hemodialysis lowering ammonia to 27 umol/L within 6 hours. The adult CPS1D case by Yokota et al. used continuous hemodiafiltration with rapid clinical improvement.

Mechanism Target:

INHIBITS Hyperammonemia-driven neurotoxicity — Dialysis rapidly removes ammonia during severe crises, reducing the upstream driver of brain edema and encephalopathy.

Show evidence (1 reference)

PMID:33409766 SUPPORT Other

"treatment with hemodialysis can reverse encephalopathy and prevent brain edema and death"

UCD management review supports hemodialysis as an acute ammonia-removal strategy.

Target Phenotypes: Hyperammonemia ↗ Encephalopathy ↗ Cerebral edema ↗ Coma ↗

Show evidence (2 references)

PMID:39469307 SUPPORT Human Clinical

"One patient underwent hemodialysis, and one patient underwent peritoneal dialysis."

Documents use of dialysis modalities in acute CPS1D management.

PMID:40125546 SUPPORT Human Clinical

"The patient responded to pharmacotherapy and continuous hemodialysis."

Confirms hemodialysis use in acute crisis management of adult CPS1D.

Liver transplantation

Action: liver transplantation MAXO:0001175

Liver transplantation is the definitive metabolic correction for CPS1D, replacing the deficient hepatic CPS1 enzyme. Vega et al. report 100% survival among transplanted UCD survivors, with normalized protein tolerance, though neurologic sequelae persisted in 69% without progression. In the Spanish registry, transplanted UCD patients had 95.2% survival. However, transplantation does not reverse pre-existing neurodevelopmental injury.

Mechanism Target:

RESTORES CPS1 molecular function deficiency — Liver transplantation replaces the deficient hepatic enzyme source and provides definitive metabolic correction.

Show evidence (1 reference)

PMID:33409766 SUPPORT Other

"Liver transplantation is the definitive cure for urea cycle abnormalities."

UCD management review supports liver transplantation as definitive metabolic therapy.

RESTORES Impaired mitochondrial ureagenesis — Transplantation restores hepatic urea-cycle capacity, normalizing protein tolerance in transplanted UCD survivors.

Show evidence (1 reference)

PMID:36937980 SUPPORT Human Clinical

"transplantationwith 100% survival, normal protein tolerance and usual need of citrulline supplementation."

Transplant cohort supports metabolic success with normal protein tolerance.

Target Phenotypes: Hyperammonemia ↗ Encephalopathy ↗

Show evidence (2 references)

PMID:36937980 SUPPORT Human Clinical

"16 (59%) received liver transplantationwith 100% survival, normal protein tolerance and usual need of citrulline supplementation."

Quantifies liver transplant outcomes in a UCD cohort including CPS1D patients.

PMID:40218931 SUPPORT Human Clinical

"Among transplanted patients (20.6%), survival was 95.2%, with no significant neurological differences compared to non-transplanted patients."

Registry-scale transplant survival data for UCDs.

Genetic counseling

Action: genetic counseling MAXO:0000079

Genetic counseling is recommended for affected families, including discussion of autosomal recessive inheritance, 25% recurrence risk for each pregnancy, carrier testing for family members, and options for prenatal or preimplantation genetic diagnosis.

Show evidence (1 reference)

PMID:37365635 SUPPORT Human Clinical

"It also provides a preliminary understanding of the relationship between genotype and phenotype, based on a summary of previous studies, which reminds us that it may help to explore the pathogenesis of the disease and contribute to genetic counselling and prenatal diagnosis."

Directly supports the role of genetic counseling and prenatal diagnosis in CPS1D families.

🔬

Biochemical Markers

5

Plasma ammonia (INCREASED)

Context: Hyperammonemia is the cardinal biochemical abnormality in CPS1D. Peak ammonia values range widely from 160 to over 1000 umol/L depending on disease severity and triggers. Ammonia levels correlate with mortality and neurological outcomes.

Pathograph Readouts

Readout Of Impaired mitochondrial ureagenesis Positive Diagnostic

Increased plasma ammonia reports failure of CPS1-dependent hepatic ammonia detoxification through the urea cycle.

Correlates With Hyperammonemia-driven neurotoxicity Positive Prognostic

Higher ammonia concentrations track the risk of encephalopathy, cerebral edema, death, and long-term neurologic injury.

Show evidence (2 references)

PMID:39174957 SUPPORT Human Clinical

"Peak blood ammonia levels ranged from 160 to 1,000 µmol/L."

Quantifies ammonia elevation across a CPS1D cohort.

PMID:40218931 SUPPORT Human Clinical

"The median ammonia level in deceased patients was higher at 1058 µmol/L (IQR 410-1793) than in survivors at 294 µmol/L (IQR 71-494)"

Registry data correlating ammonia severity with outcomes.

Plasma citrulline (DECREASED)

Context: Low plasma citrulline is a hallmark diagnostic marker of proximal urea cycle disorders including CPS1D, reflecting reduced flux through the CPS1-catalyzed step. Citrulline is used in biochemical screening and may be supplemented therapeutically.

Pathograph Readouts

Readout Of Impaired mitochondrial ureagenesis Negative Diagnostic

Low citrulline reports reduced flux from carbamoyl phosphate into downstream urea-cycle intermediate synthesis.

Show evidence (1 reference)

PMID:40125546 SUPPORT Human Clinical

"Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels."

Directly supports decreased citrulline as a biochemical finding in CPS1D.

Plasma glutamine (INCREASED)

Context: Elevated plasma glutamine serves as a compensatory nitrogen buffer and clinical index of total nitrogen load when ureagenesis is impaired. Glutamine monitoring is used to guide treatment and assess metabolic control.

Pathograph Readouts

Readout Of Compensatory nitrogen buffering as glutamine Positive Monitoring

Elevated glutamine reports compensatory storage of excess nitrogen when ureagenesis is impaired.

Show evidence (1 reference)

PMID:40125546 SUPPORT Human Clinical

"Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels."

Directly supports elevated glutamine in CPS1D.

Urinary orotic acid (NORMAL_OR_DECREASED)

Context: Normal or low urinary orotic acid excretion is a key diagnostic feature distinguishing CPS1D (and NAGS deficiency) from OTC deficiency, in which orotic acid is typically elevated due to carbamoyl phosphate overflow into pyrimidine biosynthesis.

Pathograph Readouts

Readout Of Impaired mitochondrial ureagenesis Threshold Dependent Diagnostic

Normal or low urinary orotic acid helps localize the hyperammonemic block to a proximal urea-cycle defect such as CPS1D rather than OTC deficiency.

Show evidence (1 reference)

PMID:29364180 SUPPORT Other

"Clinically and biochemically, NAGSD is indistinguishable from CPS1 deficiency (CPS1D), and common biochemical features include increased amounts of plasma ammonia and glutamine, reduced plasma citrulline, and normal or low levels of urinary orotic acid"

Review of proximal urea-cycle defects supports normal or low urinary orotic acid as part of the CPS1D/NAGSD biochemical pattern.

Plasma alanine (INCREASED)

Context: Alanine elevation is a secondary finding in some CPS1D patients, reflecting nitrogen handling imbalance and catabolic stress. An adolescent-onset case showed alanine of 757 umol/L (elevated above normal range).

Pathograph Readouts

Correlates With Hyperammonemia-driven neurotoxicity Positive Diagnostic

Elevated alanine can accompany late-onset hyperammonemic decompensation, but is a secondary marker rather than the core diagnostic signature.

Show evidence (1 reference)

PMID:37365635 SUPPORT Human Clinical

"Blood genetic metabolic screening showed elevated blood alanine (757.06umol/L; reference range 148.8 ~ 739.74umol/L)"

Quantitative documentation of elevated alanine in a late-onset CPS1D case.

{ }

Source YAML

click to show

name: Carbamoyl Phosphate Synthetase I Deficiency
category: Mendelian
creation_date: '2025-06-12T20:16:27Z'
updated_date: '2026-05-21T02:02:57Z'
synonyms:
- CPS1 deficiency
- CPS1D
- Carbamoyl phosphate synthase I deficiency
- Hyperammonemia due to CPS1 deficiency
description: 'Carbamoyl phosphate synthetase I (CPS1) deficiency is a rare autosomal recessive proximal urea cycle disorder caused by biallelic pathogenic variants in the CPS1 gene. CPS1 catalyzes the first and rate-limiting step of the urea cycle in hepatocyte mitochondria, condensing ammonia and bicarbonate into carbamoyl phosphate. Loss of CPS1 activity causes failure of hepatic ammonia detoxification, leading to systemic hyperammonemia, low plasma citrulline, elevated plasma glutamine, and characteristically normal or low urinary orotic acid. Ammonia crosses the blood-brain barrier and is detoxified to glutamine in astrocytes, causing intracellular glutamine accumulation, astrocyte swelling, cerebral edema, seizures, and long-term neurocognitive injury. CPS1D presents as a severe neonatal-onset form with acute hyperammonemic crisis or a milder late-onset form with residual enzyme activity. The Spanish UCD registry reports CPS1D mortality of 36.8%, the highest among urea cycle disorders, with neurological impairment in approximately 58% of cases.

  '
disease_term:
  preferred_term: carbamoyl phosphate synthetase I deficiency disease
  term:
    id: MONDO:0009376
    label: carbamoyl phosphate synthetase I deficiency disease
parents:
- Urea Cycle Disorder
- Inborn Error of Metabolism
pathophysiology:
- name: CPS1 molecular function deficiency
  description: 'Biallelic pathogenic variants in CPS1 reduce mitochondrial carbamoyl phosphate synthetase catalytic activity.

    '
  genes:
  - preferred_term: CPS1
    term:
      id: hgnc:2323
      label: CPS1
  molecular_functions:
  - preferred_term: carbamoyl-phosphate synthase (ammonia) activity
    term:
      id: GO:0004087
      label: carbamoyl-phosphate synthase (ammonia) activity
    modifier: DECREASED
  biological_processes:
  - preferred_term: carbamoyl phosphate biosynthetic process
    term:
      id: GO:0070409
      label: carbamoyl phosphate biosynthetic process
    modifier: DECREASED
  cell_types:
  - preferred_term: hepatocyte
    term:
      id: CL:0000182
      label: hepatocyte
  locations:
  - preferred_term: mitochondrion
    term:
      id: GO:0005739
      label: mitochondrion
  evidence:
  - reference: PMID:39469307
    reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CPS1 is an enzyme in the urea cycle that catalyzes ammonia and bicarbonate condensation.
    explanation: Supports CPS1 catalytic dysfunction as the initiating molecular event.
  downstream:
  - target: Impaired mitochondrial ureagenesis
    description: Reduced CPS1 activity blocks carbamoyl phosphate generation and proximal urea-cycle flux.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39469307
      reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: CPS1 is an enzyme in the urea cycle that catalyzes ammonia and bicarbonate condensation.
      explanation: The abstract identifies CPS1 catalytic activity at the urea-cycle entry step.
- name: Impaired mitochondrial ureagenesis
  description: 'Reduced CPS1 function in hepatic mitochondria impairs ATP-dependent condensation of ammonia and bicarbonate into carbamoyl phosphate, the first and rate-limiting step of the urea cycle. This blocks hepatic nitrogen disposal and causes systemic ammonia accumulation. The reaction is functionally dependent on N-acetylglutamate (NAG) as an essential allosteric activator.

    '
  biological_processes:
  - preferred_term: urea cycle
    term:
      id: GO:0000050
      label: urea cycle
  chemical_entities:
  - preferred_term: ammonia
    term:
      id: CHEBI:16134
      label: ammonia
    modifier: INCREASED
  - preferred_term: carbamoyl phosphate
    term:
      id: CHEBI:17672
      label: carbamoyl phosphate
    modifier: DECREASED
  - preferred_term: citrulline
    term:
      id: CHEBI:18211
      label: citrulline
    modifier: DECREASED
  locations:
  - preferred_term: liver
    term:
      id: UBERON:0002107
      label: liver
  evidence:
  - reference: PMID:39469307
    reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive.
    explanation: Supports severe hyperammonemic consequences downstream of impaired proximal ureagenesis.
  - reference: PMID:40710547
    reference_title: "Amino Acid Metabolism in Liver Mitochondria: From Homeostasis to Disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Hepatic mitochondria play critical roles in sustaining systemic nutrient balance, nitrogen detoxification, and cellular bioenergetics.
    explanation: Review supporting the role of hepatic mitochondria in nitrogen detoxification via the urea cycle.
  downstream:
  - target: Plasma ammonia
    description: Failed CPS1-dependent ureagenesis prevents ammonia disposal and elevates circulating ammonia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39469307
      reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Ammonia must be detoxified, and the urea cycle converts ammonia into urea.
      explanation: The review directly connects urea-cycle function to ammonia detoxification.
  - target: Plasma citrulline
    description: Proximal urea-cycle block reduces carbamoyl phosphate entry into downstream citrulline synthesis.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40125546
      reference_title: "Carbamoyl phosphate synthetase 1 deficiency manifested in an adult treated with prednisone for polymyositis, and cured by live-donor liver transplantation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels.
      explanation: The adult CPS1D case documents the expected low-citrulline biochemical pattern.
  - target: Urinary orotic acid
    description: Proximal carbamoyl phosphate deficiency limits overflow into pyrimidine synthesis, leaving urinary orotic acid normal or low rather than elevated.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:29364180
      reference_title: "Late-Onset N-Acetylglutamate Synthase Deficiency: Report of a Paradigmatic Adult Case Presenting with Headaches and Review of the Literature."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Clinically and biochemically, NAGSD is indistinguishable from CPS1 deficiency (CPS1D), and common biochemical features include increased amounts of plasma ammonia and glutamine, reduced plasma citrulline, and normal or low levels of urinary orotic acid
      explanation: This review states that CPS1D shares the proximal urea-cycle biochemical pattern of normal or low urinary orotic acid.
  - target: Hyperammonemia
    description: Ammonia accumulation from impaired ureagenesis manifests as hyperammonemia.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:39174957
      reference_title: Clinical features and CPS1 variants in Chinese patients with carbamoyl phosphate synthetase 1 deficiency.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Peak blood ammonia levels ranged from 160 to 1,000 µmol/L.
      explanation: CPS1D cohort data quantify hyperammonemia downstream of the proximal urea-cycle defect.
  - target: Hyperammonemia-driven neurotoxicity
    description: Systemic ammonia accumulation exposes the brain to ammonia neurotoxicity.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39469307
      reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive.
      explanation: The cohort review links CPS1D hyperammonemia to neurologic injury.
  - target: Compensatory nitrogen buffering as glutamine
    description: Nitrogen that cannot be cleared as urea is buffered in amino acids, especially glutamine.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:40125546
      reference_title: "Carbamoyl phosphate synthetase 1 deficiency manifested in an adult treated with prednisone for polymyositis, and cured by live-donor liver transplantation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels.
      explanation: Elevated glutamine supports compensatory nitrogen buffering when ureagenesis is impaired.
- name: Hyperammonemia-driven neurotoxicity
  description: 'Failure of hepatic ureagenesis causes systemic hyperammonemia. Ammonia is specifically neurotoxic and readily crosses the blood-brain barrier. In astrocytes, ammonia is detoxified to glutamine via glutamine synthetase, leading to excessive intracellular glutamine accumulation. This causes osmotic astrocyte swelling, cerebral edema, raised intracranial pressure, and encephalopathy. Hyperammonemia may also interfere with mitochondrial function and neurotransmission.

    '
  biological_processes:
  - preferred_term: glutamine biosynthetic process
    term:
      id: GO:1901704
      label: L-glutamine biosynthetic process
  - preferred_term: cellular response to nitrogen compound
    term:
      id: GO:1901699
      label: cellular response to nitrogen compound
  - preferred_term: cellular response to osmotic stress
    term:
      id: GO:0071470
      label: cellular response to osmotic stress
  chemical_entities:
  - preferred_term: ammonia
    term:
      id: CHEBI:16134
      label: ammonia
    modifier: INCREASED
  - preferred_term: glutamine
    term:
      id: CHEBI:28300
      label: glutamine
    modifier: INCREASED
  cell_types:
  - preferred_term: astrocyte
    term:
      id: CL:0000127
      label: astrocyte
  locations:
  - preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  evidence:
  - reference: PMID:39469307
    reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive.
    explanation: Supports hyperammonemia-linked neurological injury in CPS1D; cellular astrocyte swelling details are inferred from established ammonia neurotoxicity mechanisms.
  - reference: PMID:33409766
    reference_title: "Management of late onset urea cycle disorders-a remaining challenge for the intensivist?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Ammonia diffuses freely across the blood–brain barrier and is converted with alanine to glutamine by glutamine synthase. Glutamine is the main intracellular osmole of the brain. Its accumulation causes the swelling of astrocytes during hyperammonemia
    explanation: This UCD review supports the blood-brain-barrier crossing and astrocyte glutamine osmolyte mechanism.
  downstream:
  - target: Encephalopathy
    description: Hyperammonemia produces acute neurologic dysfunction that can progress from confusion to unconsciousness.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40125546
      reference_title: "Carbamoyl phosphate synthetase 1 deficiency manifested in an adult treated with prednisone for polymyositis, and cured by live-donor liver transplantation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: the patient, without apparent cause, suddenly developed confusion progressing to unconsciousness and coma.
      explanation: This adult CPS1D crisis demonstrates hyperammonemic encephalopathy progression.
  - target: Cerebral edema
    description: Severe ammonia neurotoxicity can produce cerebral edema through osmotic astrocyte injury.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:33409766
      reference_title: "Management of late onset urea cycle disorders-a remaining challenge for the intensivist?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: emergent hemodialysis is mandatory before referral to a reference center if ammonia levels are above 200 µmol/l as the risk of cerebral edema is then above 55%.
      explanation: The UCD review links severe hyperammonemia to cerebral edema risk.
  - target: Coma
    description: Severe hyperammonemic encephalopathy can progress to coma.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40125546
      reference_title: "Carbamoyl phosphate synthetase 1 deficiency manifested in an adult treated with prednisone for polymyositis, and cured by live-donor liver transplantation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: the patient, without apparent cause, suddenly developed confusion progressing to unconsciousness and coma.
      explanation: The case directly supports coma as a severe endpoint of CPS1D encephalopathy.
  - target: Seizures
    description: Hyperammonemic decompensation can provoke seizures during acute neonatal or late-onset crises.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:28658158
      reference_title: "Neonatal-onset carbamoyl phosphate synthetase I deficiency: A case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Then seizure and tachypnoea reappeared as intravenous amino acids were provided. Further examination indicated severe hyperammonemia (serum ammonia level >500mmol/L)."
      explanation: Neonatal CPS1D case directly links seizure recurrence with severe hyperammonemia.
  - target: Lethargy
    description: Neonatal hyperammonemic illness often begins with reduced alertness before progressing to coma.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:27860485
      reference_title: "An update on the use of benzoate, phenylacetate and phenylbutyrate ammonia scavengers for interrogating and modifying liver nitrogen metabolism and its implications in urea cycle disorders and liver disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: When presenting in the neonatal period, typically after a variable symptom-free interval, UCDs are characterized by overwhelming illness that rapidly progresses from poor feeding, vomiting, lethargy and/or irritability to coma and/or death
      explanation: UCD review supports lethargy as part of neonatal hyperammonemic deterioration.
  - target: Hypotonia
    description: Hyperammonemic metabolic crises can manifest with reduced muscle tone as part of acute neonatal neurologic decompensation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:25875215
      reference_title: "The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency
      explanation: The E-IMD patient registry reports muscular hypotonia during acute OAD/UCD metabolic crises and identifies carbamylphosphate 1 synthetase deficiency among disorders with frequent neonatal onset.
  - target: Vomiting
    description: Vomiting is part of the acute systemic presentation of neonatal urea-cycle decompensation.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:27860485
      reference_title: "An update on the use of benzoate, phenylacetate and phenylbutyrate ammonia scavengers for interrogating and modifying liver nitrogen metabolism and its implications in urea cycle disorders and liver disease."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: When presenting in the neonatal period, typically after a variable symptom-free interval, UCDs are characterized by overwhelming illness that rapidly progresses from poor feeding, vomiting, lethargy and/or irritability to coma and/or death
      explanation: UCD review supports vomiting as a common early sign of neonatal hyperammonemic decompensation.
  - target: Global developmental delay
    description: Recurrent or severe early hyperammonemia can leave permanent developmental sequelae.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39469307
      reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: One patient had recurrent hyperammonemia episodes in her first year of life, which led to microcephaly and global developmental delay.
      explanation: CPS1D cohort directly links recurrent hyperammonemia to global developmental delay.
  - target: Intellectual disability
    description: Long-term cognitive impairment can follow neonatal crises or present in late-onset CPS1D.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39174957
      reference_title: "Clinical features and CPS1 variants in Chinese patients with carbamoyl phosphate synthetase 1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets.
      explanation: CPS1D cohort supports intellectual disability in late-onset disease.
  - target: Microcephaly
    description: Early recurrent hyperammonemia can impair brain growth and lead to microcephaly.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39469307
      reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: One patient had recurrent hyperammonemia episodes in her first year of life, which led to microcephaly and global developmental delay.
      explanation: CPS1D cohort directly documents microcephaly after recurrent infantile hyperammonemia.
  - target: Abnormal cerebral white matter morphology
    description: Hyperammonemic CPS1D crises can be accompanied by diffuse white matter injury on MRI.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:28658158
      reference_title: "Neonatal-onset carbamoyl phosphate synthetase I deficiency: A case report."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Brain MRI showed diffused white matter lesions.
      explanation: Neonatal CPS1D case directly documents diffuse white matter lesions during severe hyperammonemia.
  - target: Atypical behavior
    description: Partial CPS1D can manifest with psychiatric or behavioral symptoms during late-onset disease.
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    evidence:
    - reference: PMID:39174957
      reference_title: "Clinical features and CPS1 variants in Chinese patients with carbamoyl phosphate synthetase 1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets.
      explanation: CPS1D cohort supports psychiatric symptoms as a late-onset manifestation.
- name: Compensatory nitrogen buffering as glutamine
  description: 'When urea synthesis is blocked, the body compensates by storing excess nitrogen as glutamine. Plasma glutamine rises as a major nitrogen carrier and serves as a clinical index of total nitrogen load.

    '
  biological_processes:
  - preferred_term: urea cycle
    term:
      id: GO:0000050
      label: urea cycle
  chemical_entities:
  - preferred_term: glutamine
    term:
      id: CHEBI:28300
      label: glutamine
    modifier: INCREASED
  evidence:
  - reference: PMID:39469307
    reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Ammonia results from amino acid turnover and is produced by intestinal urease-positive bacteria. Ammonia must be detoxified, and the urea cycle converts ammonia into urea.
    explanation: Supports the role of the urea cycle in ammonia disposal and the consequence of its disruption.
  - reference: PMID:40125546
    reference_title: "Carbamoyl phosphate synthetase 1 deficiency manifested in an adult treated with prednisone for polymyositis, and cured by live-donor liver transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels.
    explanation: Confirms the characteristic biochemical pattern of low citrulline and high glutamine in CPS1D.
  downstream:
  - target: Plasma glutamine
    description: Excess nitrogen is buffered as glutamine, elevating plasma glutamine.
    causal_link_type: DIRECT
    evidence:
    - reference: PMID:40125546
      reference_title: "Carbamoyl phosphate synthetase 1 deficiency manifested in an adult treated with prednisone for polymyositis, and cured by live-donor liver transplantation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels.
      explanation: The case directly documents high glutamine in CPS1D.
phenotypes:
- name: Hyperammonemia
  description: 'Elevated plasma ammonia is the hallmark of CPS1D, occurring during both baseline disease activity and catabolic stress. In the Spanish registry, median ammonia in deceased UCD patients was 1058 umol/L versus 294 umol/L in survivors. Peak ammonia values in CPS1D cohorts range from 160 to over 1000 umol/L.

    '
  phenotype_term:
    preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:39174957
    reference_title: "Clinical features and CPS1 variants in Chinese patients with carbamoyl phosphate synthetase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Peak blood ammonia levels ranged from 160 to 1,000 µmol/L.
    explanation: Quantifies the range of hyperammonemia severity across a CPS1D cohort.
  - reference: PMID:40218931
    reference_title: "Understanding the Natural History and the Effects of Current Therapeutic Strategies on Urea Cycle Disorders: Insights from the UCD Spanish Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The median ammonia level in deceased patients was higher at 1058 µmol/L (IQR 410-1793) than in survivors at 294 µmol/L (IQR 71-494)
    explanation: Spanish registry data showing ammonia severity correlates with mortality.
- name: Encephalopathy
  description: 'Acute or recurrent neurologic dysfunction due to ammonia neurotoxicity, manifesting as lethargy progressing to confusion, unconsciousness, and coma. Cerebral edema can develop when ammonia levels exceed 200 umol/L.

    '
  phenotype_term:
    preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:39469307
    reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: CPS1 deficiency presents in the neonatal period with hyperammonemia, resulting in death or neurological sequelae if patients survive.
    explanation: Supports encephalopathy as a direct consequence of hyperammonemia in CPS1D.
  - reference: PMID:40125546
    reference_title: "Carbamoyl phosphate synthetase 1 deficiency manifested in an adult treated with prednisone for polymyositis, and cured by live-donor liver transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the patient, without apparent cause, suddenly developed confusion progressing to unconsciousness and coma.
    explanation: Case report demonstrating acute encephalopathy progression in adult-onset CPS1D.
- name: Seizures
  description: 'Seizures occur in CPS1D during hyperammonemic crises. They may correlate with rising glutamine levels even before blood ammonia concentrations peak, and can persist after ammonia normalization.

    '
  phenotype_term:
    preferred_term: Seizure
    term:
      id: HP:0001250
      label: Seizure
  evidence:
  - reference: PMID:28658158
    reference_title: "Neonatal-onset carbamoyl phosphate synthetase I deficiency: A case report."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Then seizure and tachypnoea reappeared as intravenous amino acids were provided. Further examination indicated severe hyperammonemia (serum ammonia level >500mmol/L)."
    explanation: Directly documents seizure during severe neonatal CPS1D hyperammonemia.
- name: Coma
  description: 'Severe hyperammonemic encephalopathy in CPS1D can progress to unconsciousness and coma during metabolic decompensation.

    '
  phenotype_term:
    preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
  evidence:
  - reference: PMID:40125546
    reference_title: "Carbamoyl phosphate synthetase 1 deficiency manifested in an adult treated with prednisone for polymyositis, and cured by live-donor liver transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: the patient, without apparent cause, suddenly developed confusion progressing to unconsciousness and coma.
    explanation: The adult-onset CPS1D case directly documents coma during hyperammonemic decompensation.
- name: Global developmental delay
  description: 'Developmental delay and neurocognitive impairment are common in CPS1D survivors, associated with peak ammonia levels, duration of hyperammonemia, and frequency of recurrent crises. In the Spanish registry, neurological impairment occurred in 58% of CPS1D patients.

    '
  phenotype_term:
    preferred_term: Global developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:39469307
    reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One patient had recurrent hyperammonemia episodes in her first year of life, which led to microcephaly and global developmental delay.
    explanation: Directly documents global developmental delay resulting from recurrent hyperammonemia in CPS1D.
  - reference: PMID:40218931
    reference_title: "Understanding the Natural History and the Effects of Current Therapeutic Strategies on Urea Cycle Disorders: Insights from the UCD Spanish Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Neurological impairment occurred in 44% of patients, with worse neurological outcomes observed in patients with argininosuccinate lyase deficiency, arginase 1 deficiency, hyperornithinemia-hyperammonemia-homocitrullinuria, EO presentations, pre-2014 diagnosis, and patients with higher levels of ammonia at diagnosis.
    explanation: Registry data demonstrating high rates of neurological impairment in UCDs including CPS1D.
- name: Intellectual disability
  description: 'Intellectual disability is a long-term sequela in CPS1D survivors, particularly those with neonatal-onset disease or recurrent severe hyperammonemic episodes. Late-onset cases may present with mental retardation and psychiatric symptoms.

    '
  phenotype_term:
    preferred_term: Intellectual disability
    term:
      id: HP:0001249
      label: Intellectual disability
  evidence:
  - reference: PMID:39174957
    reference_title: "Clinical features and CPS1 variants in Chinese patients with carbamoyl phosphate synthetase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets.
    explanation: Directly supports intellectual disability as a presenting feature in late-onset CPS1D.
- name: Hypotonia
  description: 'Neonatal hypotonia is a common early sign during hyperammonemic crises in CPS1D, often accompanying poor feeding and lethargy.

    '
  phenotype_term:
    preferred_term: Hypotonia
    term:
      id: HP:0001252
      label: Hypotonia
  evidence:
  - reference: PMID:25875215
    reference_title: "The phenotypic spectrum of organic acidurias and urea cycle disorders. Part 1: the initial presentation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: vomiting and/or muscular hypotonia. Neonatal onset of symptoms was most frequent in argininosuccinic synthetase and lyase deficiency and carbamylphosphate 1 synthetase deficiency
    explanation: Human registry data list muscular hypotonia during acute OAD/UCD metabolic crises and name carbamylphosphate 1 synthetase deficiency among disorders with frequent neonatal onset.
  notes: >
    The disease-specific CPS1D abstracts support neonatal hyperammonemic
    neurologic deterioration, while the broader E-IMD OAD/UCD registry abstract
    provides the exact quotable support for muscular hypotonia during acute
    metabolic crises.
- name: Vomiting
  description: 'Recurrent vomiting occurs during metabolic decompensation episodes, often triggered by catabolic stress such as infection or dehydration.

    '
  phenotype_term:
    preferred_term: Vomiting
    term:
      id: HP:0002013
      label: Vomiting
  notes: Vomiting is a well-recognized feature of acute hyperammonemic crises in UCDs but specific quantitative data for CPS1D from the available abstracts is limited.
  evidence:
  - reference: PMID:27860485
    reference_title: "An update on the use of benzoate, phenylacetate and phenylbutyrate ammonia scavengers for interrogating and modifying liver nitrogen metabolism and its implications in urea cycle disorders and liver disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: When presenting in the neonatal period, typically after a variable symptom-free interval, UCDs are characterized by overwhelming illness that rapidly progresses from poor feeding, vomiting, lethargy and/or irritability to coma and/or death
    explanation: UCD review supports vomiting during neonatal hyperammonemic decompensation.
- name: Lethargy
  description: 'Decreased alertness and lethargy during acute hyperammonemic episodes, which may progress to coma if ammonia levels are not rapidly reduced.

    '
  phenotype_term:
    preferred_term: Lethargy
    term:
      id: HP:0001254
      label: Lethargy
  evidence:
  - reference: PMID:27860485
    reference_title: "An update on the use of benzoate, phenylacetate and phenylbutyrate ammonia scavengers for interrogating and modifying liver nitrogen metabolism and its implications in urea cycle disorders and liver disease."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: When presenting in the neonatal period, typically after a variable symptom-free interval, UCDs are characterized by overwhelming illness that rapidly progresses from poor feeding, vomiting, lethargy and/or irritability to coma and/or death
    explanation: UCD review supports lethargy during neonatal hyperammonemic deterioration.
- name: Microcephaly
  description: 'Microcephaly may develop as a consequence of recurrent hyperammonemic episodes and associated brain injury during infancy.

    '
  phenotype_term:
    preferred_term: Microcephaly
    term:
      id: HP:0000252
      label: Microcephaly
  evidence:
  - reference: PMID:39469307
    reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One patient had recurrent hyperammonemia episodes in her first year of life, which led to microcephaly and global developmental delay.
    explanation: Directly documents microcephaly resulting from recurrent hyperammonemia in a CPS1D patient.
- name: Cerebral edema
  description: 'Cerebral edema can develop due to hyperammonemia when ammonia levels exceed approximately 200 umol/L. It results from astrocytic glutamine accumulation and osmotic swelling, and represents a life-threatening complication requiring urgent ammonia reduction.

    '
  phenotype_term:
    preferred_term: Cerebral edema
    term:
      id: HP:0002181
      label: Cerebral edema
  evidence:
  - reference: PMID:33409766
    reference_title: "Management of late onset urea cycle disorders-a remaining challenge for the intensivist?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: emergent hemodialysis is mandatory before referral to a reference center if ammonia levels are above 200 µmol/l as the risk of cerebral edema is then above 55%.
    explanation: Supports cerebral edema risk when hyperammonemia is severe in urea-cycle disorders.
- name: Abnormal cerebral white matter morphology
  description: 'White matter lesions on brain MRI have been reported in late-onset CPS1D, reflecting chronic or recurrent hyperammonemia-related brain injury.

    '
  phenotype_term:
    preferred_term: Abnormal cerebral white matter morphology
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  evidence:
  - reference: PMID:37365635
    reference_title: "Clinical and genetic analysis of a case of late onset carbamoyl phosphate synthase I deficiency caused by CPS1 mutation and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: MRI of the brain showed diffuse white matter lesions.
    explanation: Directly documents white matter lesions on MRI in a late-onset CPS1D case.
- name: Atypical behavior
  description: 'Late-onset CPS1D may present with psychiatric symptoms and behavioral abnormalities, which can lead to misdiagnosis before metabolic workup is performed.

    '
  phenotype_term:
    preferred_term: Atypical behavior
    term:
      id: HP:0000708
      label: Atypical behavior
  evidence:
  - reference: PMID:39174957
    reference_title: "Clinical features and CPS1 variants in Chinese patients with carbamoyl phosphate synthetase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The remaining four patients had late-onset CPS1 deficiency, presenting with mental retardation, psychiatric symptoms, and self-selected low-protein diets.
    explanation: Directly supports psychiatric/behavioral symptoms as a feature of late-onset CPS1D.
biochemical:
- name: Plasma ammonia
  presence: INCREASED
  context: 'Hyperammonemia is the cardinal biochemical abnormality in CPS1D. Peak ammonia values range widely from 160 to over 1000 umol/L depending on disease severity and triggers. Ammonia levels correlate with mortality and neurological outcomes.

    '
  readouts:
  - target: Impaired mitochondrial ureagenesis
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Increased plasma ammonia reports failure of CPS1-dependent hepatic
      ammonia detoxification through the urea cycle.
  - target: Hyperammonemia-driven neurotoxicity
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: PROGNOSTIC
    interpretation: >
      Higher ammonia concentrations track the risk of encephalopathy, cerebral
      edema, death, and long-term neurologic injury.
  biomarker_term:
    preferred_term: ammonia
    term:
      id: CHEBI:16134
      label: ammonia
  evidence:
  - reference: PMID:39174957
    reference_title: "Clinical features and CPS1 variants in Chinese patients with carbamoyl phosphate synthetase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Peak blood ammonia levels ranged from 160 to 1,000 µmol/L.
    explanation: Quantifies ammonia elevation across a CPS1D cohort.
  - reference: PMID:40218931
    reference_title: "Understanding the Natural History and the Effects of Current Therapeutic Strategies on Urea Cycle Disorders: Insights from the UCD Spanish Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The median ammonia level in deceased patients was higher at 1058 µmol/L (IQR 410-1793) than in survivors at 294 µmol/L (IQR 71-494)
    explanation: Registry data correlating ammonia severity with outcomes.
- name: Plasma citrulline
  presence: DECREASED
  context: 'Low plasma citrulline is a hallmark diagnostic marker of proximal urea cycle disorders including CPS1D, reflecting reduced flux through the CPS1-catalyzed step. Citrulline is used in biochemical screening and may be supplemented therapeutically.

    '
  readouts:
  - target: Impaired mitochondrial ureagenesis
    relationship: READOUT_OF
    direction: NEGATIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Low citrulline reports reduced flux from carbamoyl phosphate into
      downstream urea-cycle intermediate synthesis.
  biomarker_term:
    preferred_term: citrulline
    term:
      id: CHEBI:18211
      label: citrulline
  evidence:
  - reference: PMID:40125546
    reference_title: "Carbamoyl phosphate synthetase 1 deficiency manifested in an adult treated with prednisone for polymyositis, and cured by live-donor liver transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels.
    explanation: Directly supports decreased citrulline as a biochemical finding in CPS1D.
- name: Plasma glutamine
  presence: INCREASED
  context: 'Elevated plasma glutamine serves as a compensatory nitrogen buffer and clinical index of total nitrogen load when ureagenesis is impaired. Glutamine monitoring is used to guide treatment and assess metabolic control.

    '
  readouts:
  - target: Compensatory nitrogen buffering as glutamine
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: MONITORING
    interpretation: >
      Elevated glutamine reports compensatory storage of excess nitrogen when
      ureagenesis is impaired.
  biomarker_term:
    preferred_term: glutamine
    term:
      id: CHEBI:28300
      label: glutamine
  evidence:
  - reference: PMID:40125546
    reference_title: "Carbamoyl phosphate synthetase 1 deficiency manifested in an adult treated with prednisone for polymyositis, and cured by live-donor liver transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Plasma amino acid analysis revealed decreased citrulline levels and elevated glutamine levels.
    explanation: Directly supports elevated glutamine in CPS1D.
- name: Urinary orotic acid
  presence: NORMAL_OR_DECREASED
  context: 'Normal or low urinary orotic acid excretion is a key diagnostic feature distinguishing CPS1D (and NAGS deficiency) from OTC deficiency, in which orotic acid is typically elevated due to carbamoyl phosphate overflow into pyrimidine biosynthesis.

    '
  notes: Normal or low urinary orotic acid is a key diagnostic feature distinguishing CPS1D from OTC deficiency, though direct documentation in the available abstracts is limited.
  readouts:
  - target: Impaired mitochondrial ureagenesis
    relationship: READOUT_OF
    direction: THRESHOLD_DEPENDENT
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Normal or low urinary orotic acid helps localize the hyperammonemic block
      to a proximal urea-cycle defect such as CPS1D rather than OTC deficiency.
  biomarker_term:
    preferred_term: orotic acid
    term:
      id: CHEBI:16742
      label: orotic acid
  evidence:
  - reference: PMID:29364180
    reference_title: "Late-Onset N-Acetylglutamate Synthase Deficiency: Report of a Paradigmatic Adult Case Presenting with Headaches and Review of the Literature."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Clinically and biochemically, NAGSD is indistinguishable from CPS1 deficiency (CPS1D), and common biochemical features include increased amounts of plasma ammonia and glutamine, reduced plasma citrulline, and normal or low levels of urinary orotic acid
    explanation: >
      Review of proximal urea-cycle defects supports normal or low urinary
      orotic acid as part of the CPS1D/NAGSD biochemical pattern.
- name: Plasma alanine
  presence: INCREASED
  notes: 'Elevated in some CPS1D cases, reflecting secondary amino acid changes during catabolic stress. Not always elevated.

    '
  context: 'Alanine elevation is a secondary finding in some CPS1D patients, reflecting nitrogen handling imbalance and catabolic stress. An adolescent-onset case showed alanine of 757 umol/L (elevated above normal range).

    '
  readouts:
  - target: Hyperammonemia-driven neurotoxicity
    relationship: CORRELATES_WITH
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: >
      Elevated alanine can accompany late-onset hyperammonemic decompensation,
      but is a secondary marker rather than the core diagnostic signature.
  biomarker_term:
    preferred_term: alanine
    term:
      id: CHEBI:16449
      label: alanine
  evidence:
  - reference: PMID:37365635
    reference_title: "Clinical and genetic analysis of a case of late onset carbamoyl phosphate synthase I deficiency caused by CPS1 mutation and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Blood genetic metabolic screening showed elevated blood alanine (757.06umol/L; reference range 148.8 ~ 739.74umol/L)
    explanation: Quantitative documentation of elevated alanine in a late-onset CPS1D case.
genetic:
- name: CPS1 pathogenic variants
  gene_term:
    preferred_term: CPS1
    term:
      id: hgnc:2323
      label: CPS1
  features: 'CPS1D is caused by biallelic pathogenic variants in the CPS1 gene encoding carbamoyl phosphate synthetase 1, a mitochondrial urea-cycle enzyme. Extensive allelic heterogeneity exists, with many novel variants reported in 2023-2024 cohorts. Variant types include missense, frameshift, in-frame deletion, and splicing mutations. Compound heterozygosity is common. No hotspot variants have been observed. Complete loss of function typically causes severe neonatal-onset disease, while hypomorphic variants with residual enzyme activity are associated with late-onset presentations.

    '
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:39174957
      reference_title: "Clinical features and CPS1 variants in Chinese patients with carbamoyl phosphate synthetase 1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Carbamoyl phosphate synthetase 1 (CPS1) deficiency (OMIM 237300), an autosomal recessive rare and severe urea cycle disorder, is associated with hyperammonemia and high mortality.
      explanation: Directly confirms autosomal recessive inheritance of CPS1D.
  variants:
  - name: Compound heterozygous CPS1 variants (Chinese cohort)
    description: 'Dong et al. identified 12 CPS1 variants in seven Chinese CPS1D patients, including seven missense, three frameshift, one in-frame deletion, and one splicing variant. Ten of 12 variants were novel, and all patients exhibited compound heterozygosity.

      '
    evidence:
    - reference: PMID:39174957
      reference_title: "Clinical features and CPS1 variants in Chinese patients with carbamoyl phosphate synthetase 1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Among the 12 CPS1 variants identified in these patients, 10 were novel, with all patients exhibiting compound heterozygosity for CPS1 mutant alleles.
      explanation: Documents the allelic heterogeneity and compound heterozygosity pattern in CPS1D.
  - name: Homozygous c.2397G>A (p.Met799Ile) CPS1 variant
    description: 'A homozygous likely pathogenic CPS1 variant identified in a 59-year-old Japanese woman with late-onset CPS1D manifested during corticosteroid treatment for polymyositis.

      '
  - name: Compound heterozygous c.1145C>T and c.4080_c.4091del CPS1 variants
    description: 'Compound heterozygous CPS1 variants identified in an adolescent-onset case, including a missense mutation and a novel non-frameshift deletion.

      '
    evidence:
    - reference: PMID:37365635
      reference_title: "Clinical and genetic analysis of a case of late onset carbamoyl phosphate synthase I deficiency caused by CPS1 mutation and literature review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: Whole-exome sequencing revealed compound heterozygous mutations in the CPS1, a missense mutation (c.1145 C > T) and an unreported de novo non-frame shift mutation (c.4080_c.4091delAGGCATCCTGAT)
      explanation: Documents specific compound heterozygous variants in a late-onset CPS1D case.
  evidence:
  - reference: PMID:39174957
    reference_title: "Clinical features and CPS1 variants in Chinese patients with carbamoyl phosphate synthetase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: No hotspot variants were observed among the patients. Our data contribute to expanding the mutation spectrum of CPS1.
    explanation: Supports extensive allelic heterogeneity without recurrent hotspot mutations in CPS1D.
- name: CPS1
  gene_term:
    preferred_term: CPS1
    term:
      id: hgnc:2323
      label: CPS1
  association: Pathogenic Variants
  evidence:
  - reference: CGGV:assertion_dbc4dbbe-8827-4d68-a396-8368f3801e78-2018-10-12T160000.000Z
    reference_title: "CPS1 / carbamoyl phosphate synthetase I deficiency disease (Definitive)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "CPS1 | HGNC:2323 | carbamoyl phosphate synthetase I deficiency disease | MONDO:0009376 | AR | Definitive"
    explanation: ClinGen classifies the CPS1-carbamoyl phosphate synthetase I deficiency disease gene-disease relationship as definitive with autosomal recessive inheritance.
treatments:
- name: Protein-restricted diet
  description: 'Restriction of dietary protein intake is the cornerstone of chronic CPS1D management, aimed at reducing endogenous nitrogen load and preventing hyperammonemic crises. Adequate calories and essential amino acids must be maintained. In the Spanish UCD registry, 92% of medically managed patients followed protein restriction.

    '
  treatment_term:
    preferred_term: dietary intervention
    term:
      id: MAXO:0000088
      label: dietary intervention
  target_mechanisms:
  - target: Compensatory nitrogen buffering as glutamine
    treatment_effect: INHIBITS
    description: >
      Protein restriction lowers dietary nitrogen load, reducing ammonia and
      glutamine accumulation pressure when ureagenesis is impaired.
    evidence:
    - reference: PMID:38201843
      reference_title: "Long-Term Management of Patients with Mild Urea Cycle Disorders Identified through the Newborn Screening: An Expert Opinion for Clinical Practice."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: The therapy should be based on a low-protein diet and nitrogen scavengers.
      explanation: Expert consensus supports low-protein diet as a core UCD therapy.
  target_phenotypes:
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  - preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:38201843
    reference_title: "Long-Term Management of Patients with Mild Urea Cycle Disorders Identified through the Newborn Screening: An Expert Opinion for Clinical Practice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: The therapy should be based on a low-protein diet and nitrogen scavengers.
    explanation: Expert consensus supporting protein-restricted diet as foundational therapy in UCDs.
- name: Nitrogen scavenger therapy
  description: 'Sodium phenylbutyrate, glycerol phenylbutyrate, or sodium benzoate are used to provide alternative pathways for nitrogen excretion. These medications conjugate with glutamine or glycine to form renally excreted waste nitrogen compounds. Therapeutic drug monitoring of phenylbutyrate metabolites is increasingly adopted, as elevated phenylacetate concentrations above 500 ug/mL may be toxic.

    '
  treatment_term:
    preferred_term: nitrogen scavenger therapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: sodium phenylbutyrate
      term:
        id: CHEBI:75316
        label: sodium phenylbutyrate
    - preferred_term: glycerol phenylbutyrate
      term:
        id: CHEBI:134745
        label: glycerol phenylbutyrate
    - preferred_term: sodium benzoate
      term:
        id: CHEBI:113455
        label: sodium benzoate
  target_mechanisms:
  - target: Impaired mitochondrial ureagenesis
    treatment_effect: BYPASSES
    description: >
      Nitrogen scavengers provide alternative renal nitrogen-excretion routes
      that bypass the blocked urea-cycle entry step.
    evidence:
    - reference: PMID:33409766
      reference_title: "Management of late onset urea cycle disorders-a remaining challenge for the intensivist?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Ammonia is diverted to the glycine and hippuric acid pathway by benzoate, and to the glutamine and phenylacetylglutamine pathway allowing elimination in the urine without passing through the urea cycle
      explanation: UCD management review explains the bypass mechanism of benzoate and phenylacetate pathways.
  target_phenotypes:
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:37717413
    reference_title: "Monitoring the treatment of urea cycle disorders using phenylbutyrate metabolite analyses: Still many lessons to learn."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Medications that elicit an alternate pathway for nitrogen excretion such as oral sodium phenylbutyrate (NaPBA) and glycerol phenylbutyrate (GPB) and intravenous sodium phenylacetate (NaPAA) are important for the management of urea cycle disorders (UCDs).
    explanation: Directly supports nitrogen scavenger therapy as important in UCD management.
- name: Citrulline and arginine supplementation
  description: 'Supplementation with citrulline and/or arginine provides urea cycle intermediates to maximize residual ammonia excretion capacity. In a study of 79 UCD patients including CPS1D cases, mean ammonia during citrulline treatment was 35.9 umol/L versus 49.8 umol/L with arginine alone. At last evaluation, 98.7% showed normal or adapted behavior and 79.0% had normal social life.

    '
  treatment_term:
    preferred_term: nutritional supplementation
    term:
      id: MAXO:0000106
      label: nutritional supplementation
    therapeutic_agent:
    - preferred_term: citrulline
      term:
        id: CHEBI:18211
        label: citrulline
    - preferred_term: L-arginine
      term:
        id: CHEBI:16467
        label: L-arginine
  target_mechanisms:
  - target: Impaired mitochondrial ureagenesis
    treatment_effect: MODULATES
    description: >
      Citrulline and/or arginine supplementation supplies downstream urea-cycle
      intermediates to support residual nitrogen disposal.
    evidence:
    - reference: PMID:37480106
      reference_title: "Citrulline in the management of patients with urea cycle disorders."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: supplementation with amino acids involved in the urea cycle (arginine and/or citrulline, depending on the enzyme deficiency), to maximize ammonia excretion through the urea cycle
      explanation: UCD cohort paper supports amino-acid supplementation to maximize ammonia excretion.
  target_phenotypes:
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:37480106
    reference_title: "Citrulline in the management of patients with urea cycle disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: During treatment, mean ammonia concentrations were 35.9 µmol/L with citrulline, 49.8 µmol/L with arginine, and 53.0 µmol/L with arginine + citrulline.
    explanation: Quantifies ammonia control with citrulline versus arginine supplementation in UCDs.
  - reference: PMID:37480106
    reference_title: "Citrulline in the management of patients with urea cycle disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: At last evaluation, mean height and weight for age were normal and most patients showed normal or adapted behavior (98.7%) and normal social life (79.0%).
    explanation: Long-term functional outcomes supporting citrulline supplementation efficacy.
- name: Carglumic acid (N-carbamylglutamate)
  description: 'Carglumic acid is a synthetic analog of N-acetylglutamate (NAG), the essential allosteric activator of CPS1. It can restore residual urea cycle activity in patients with some remaining CPS1 enzyme, and may normalize ammonia levels. All surviving patients in the Noori et al. cohort except one were on carglumic acid, which may have contributed to their survival and disease control.

    '
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: carglumic acid
      term:
        id: CHEBI:71028
        label: carglumic acid
  target_mechanisms:
  - target: CPS1 molecular function deficiency
    treatment_effect: ACTIVATES
    description: >
      Carglumic acid is an N-acetylglutamate analog that can activate residual
      CPS1 activity in selected patients.
    evidence:
    - reference: PMID:33409766
      reference_title: "Management of late onset urea cycle disorders-a remaining challenge for the intensivist?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: It works by replacing NAG which is an essential activator of CPS1
      explanation: UCD review supports the NAG-analog mechanism for carglumic acid acting through CPS1 activation.
  target_phenotypes:
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  evidence:
  - reference: PMID:33409766
    reference_title: "Management of late onset urea cycle disorders-a remaining challenge for the intensivist?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: It works by replacing NAG which is an essential activator of CPS1
    explanation: Supports carglumic acid as a NAG analog that activates CPS1-dependent urea-cycle function.
  - reference: PMID:39469307
    reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: All patients except one were on Carglumic acid which could contribute to their survival and disease control.
    explanation: Directly supports carglumic acid use and its potential contribution to survival in CPS1D.
- name: Acute crisis management with dialysis
  description: 'During severe hyperammonemic crises, rapid extracorporeal ammonia removal by hemodialysis or continuous hemodiafiltration is essential. Noori et al. report hemodialysis lowering ammonia to 27 umol/L within 6 hours. The adult CPS1D case by Yokota et al. used continuous hemodiafiltration with rapid clinical improvement.

    '
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_mechanisms:
  - target: Hyperammonemia-driven neurotoxicity
    treatment_effect: INHIBITS
    description: >
      Dialysis rapidly removes ammonia during severe crises, reducing the
      upstream driver of brain edema and encephalopathy.
    evidence:
    - reference: PMID:33409766
      reference_title: "Management of late onset urea cycle disorders-a remaining challenge for the intensivist?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: treatment with hemodialysis can reverse encephalopathy and prevent brain edema and death
      explanation: UCD management review supports hemodialysis as an acute ammonia-removal strategy.
  target_phenotypes:
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  - preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  - preferred_term: Cerebral edema
    term:
      id: HP:0002181
      label: Cerebral edema
  - preferred_term: Coma
    term:
      id: HP:0001259
      label: Coma
  evidence:
  - reference: PMID:39469307
    reference_title: "Carbamoly-phosphate synthetase 1 (CPS1) deficiency: A tertiary center retrospective cohort study and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: One patient underwent hemodialysis, and one patient underwent peritoneal dialysis.
    explanation: Documents use of dialysis modalities in acute CPS1D management.
  - reference: PMID:40125546
    reference_title: "Carbamoyl phosphate synthetase 1 deficiency manifested in an adult treated with prednisone for polymyositis, and cured by live-donor liver transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The patient responded to pharmacotherapy and continuous hemodialysis.
    explanation: Confirms hemodialysis use in acute crisis management of adult CPS1D.
- name: Liver transplantation
  description: 'Liver transplantation is the definitive metabolic correction for CPS1D, replacing the deficient hepatic CPS1 enzyme. Vega et al. report 100% survival among transplanted UCD survivors, with normalized protein tolerance, though neurologic sequelae persisted in 69% without progression. In the Spanish registry, transplanted UCD patients had 95.2% survival. However, transplantation does not reverse pre-existing neurodevelopmental injury.

    '
  treatment_term:
    preferred_term: liver transplantation
    term:
      id: MAXO:0001175
      label: liver transplantation
  target_mechanisms:
  - target: CPS1 molecular function deficiency
    treatment_effect: RESTORES
    description: >
      Liver transplantation replaces the deficient hepatic enzyme source and
      provides definitive metabolic correction.
    evidence:
    - reference: PMID:33409766
      reference_title: "Management of late onset urea cycle disorders-a remaining challenge for the intensivist?"
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Liver transplantation is the definitive cure for urea cycle abnormalities.
      explanation: UCD management review supports liver transplantation as definitive metabolic therapy.
  - target: Impaired mitochondrial ureagenesis
    treatment_effect: RESTORES
    description: >
      Transplantation restores hepatic urea-cycle capacity, normalizing protein
      tolerance in transplanted UCD survivors.
    evidence:
    - reference: PMID:36937980
      reference_title: "Urea cycle disorders and indications for liver transplantation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: transplantationwith 100% survival, normal protein tolerance and usual need of citrulline supplementation.
      explanation: Transplant cohort supports metabolic success with normal protein tolerance.
  target_phenotypes:
  - preferred_term: Hyperammonemia
    term:
      id: HP:0001987
      label: Hyperammonemia
  - preferred_term: Encephalopathy
    term:
      id: HP:0001298
      label: Encephalopathy
  evidence:
  - reference: PMID:36937980
    reference_title: "Urea cycle disorders and indications for liver transplantation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: 16 (59%) received liver transplantationwith 100% survival, normal protein tolerance and usual need of citrulline supplementation.
    explanation: Quantifies liver transplant outcomes in a UCD cohort including CPS1D patients.
  - reference: PMID:40218931
    reference_title: "Understanding the Natural History and the Effects of Current Therapeutic Strategies on Urea Cycle Disorders: Insights from the UCD Spanish Registry."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among transplanted patients (20.6%), survival was 95.2%, with no significant neurological differences compared to non-transplanted patients.
    explanation: Registry-scale transplant survival data for UCDs.
- name: Genetic counseling
  description: 'Genetic counseling is recommended for affected families, including discussion of autosomal recessive inheritance, 25% recurrence risk for each pregnancy, carrier testing for family members, and options for prenatal or preimplantation genetic diagnosis.

    '
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:37365635
    reference_title: "Clinical and genetic analysis of a case of late onset carbamoyl phosphate synthase I deficiency caused by CPS1 mutation and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: It also provides a preliminary understanding of the relationship between genotype and phenotype, based on a summary of previous studies, which reminds us that it may help to explore the pathogenesis of the disease and contribute to genetic counselling and prenatal diagnosis.
    explanation: Directly supports the role of genetic counseling and prenatal diagnosis in CPS1D families.
prevalence:
- notes: CPS1D is one of the rarest urea cycle disorders. The incidence of all UCDs in Spain was approximately 1:36,063 births over the past decade. CPS1D represented approximately 4 of 33 patients in one transplant-center cohort. The Spanish UCD registry reported the highest mortality (36.8%) among all UCD subtypes for CPS1D.
progression:
- notes: CPS1D is divided into two clinical strata based on residual enzyme activity. Neonatal-onset (severe) disease presents within the first days of life as acute hyperammonemic crisis with encephalopathy, seizures, and high mortality. Late-onset disease presents at any age from infancy to adulthood, often triggered by catabolic stress (infection, dehydration, corticosteroids, surgery). Triggers increase endogenous protein catabolism and overwhelm residual urea cycle capacity. Long-term neurodevelopmental outcome is determined by peak ammonia levels, duration of hyperammonemia, and frequency of recurrent crises. Liver transplantation provides definitive metabolic correction but does not reverse established neurological injury.
references:
- reference: PMID:20301396
  title: Urea Cycle Disorders Overview.
  tags:
  - GeneReviews
  findings: []
notes: 'CPS1D is clinically indistinguishable from NAGS deficiency without genetic or enzymatic testing, as both are proximal urea cycle defects with similar biochemical profiles (hyperammonemia, low citrulline, high glutamine, and normal or low urinary orotic acid). NAGS deficiency may respond to carglumic acid therapy more completely since the underlying CPS1 enzyme is intact. Distinguishing CPS1D from OTC deficiency relies on urinary orotic acid levels, which are elevated in OTC deficiency but normal or low in CPS1D.

  '

📚

References & Deep Research

References

1

PMID:20301396

Urea Cycle Disorders Overview.

No top-level findings curated for this source.

Deep Research

1

Falcon ▸

Disease Pathophysiology Research Template

Edison Scientific Literature 40 citations 2026-02-23T23:41:12.152417

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)

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)

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)

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)

Biological processes (GO-style disrupted processes; labels) The evidence supports disruption of the following biological processes:
Urea cycle / ureagenesis (impaired nitrogen excretion as urea) (bakshi2025ahypomorphicmodel pages 1-3, erdal2025aminoacidmetabolism pages 10-12)
Ammonia detoxification / ammonia assimilation (failure → hyperammonemia) (noori2024carbamolyphosphatesynthetase1 pages 1-2)
Amino-acid catabolic processes and nitrogen metabolism homeostasis (system-level imbalance) (noori2024carbamolyphosphatesynthetase1 pages 1-2, erdal2025aminoacidmetabolism pages 10-12)
Astrocyte volume regulation / osmotic homeostasis (via glutamine accumulation) (shakerdi2023druginducedhyperammonaemia pages 1-2, simpson2025ureacycledisordersa pages 1-4)
Mitochondrial function and energy metabolism (hyperammonemia may interfere with mitochondrial function) (shakerdi2023druginducedhyperammonaemia pages 1-2)
Cellular components (where key processes occur)
Mitochondrial matrix (CPS1 catalysis; intramitochondrial urea cycle) (yokota2025carbamoylphosphatesynthetase pages 2-3, erdal2025aminoacidmetabolism pages 10-12)
Blood/plasma compartment (hyperammonemia; plasma glutamine/citrulline monitoring) (noori2024carbamolyphosphatesynthetase1 pages 2-3)
Central nervous system (BBB crossing; astrocyte glutamine accumulation, cerebral edema) (shakerdi2023druginducedhyperammonaemia pages 1-2, simpson2025ureacycledisordersa pages 1-4)
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)

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)

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)

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)

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)

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)

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

(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.
(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.
(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.
(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.
(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.
(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.
(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.
(simpson2025ureacycledisordersa pages 1-4): KL Simpson, EL MacLeod, and A Kakajiwala. Urea cycle disorders overview. Unknown journal, 2025.
(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.
(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.
(simpson2025ureacycledisorders pages 4-6): KL Simpson, EL MacLeod, and A Kakajiwala. Urea cycle disorders overview. Unknown journal, 2025.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.
(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.

Carbamoyl Phosphate Synthetase I Deficiency

Ask OpenScientist

OpenScientist Report

Pathophysiology

Pathograph

Phenotypes

Genetic Associations

Treatments

Biochemical Markers

Source YAML

References & Deep Research

References

Deep Research

Disease Pathophysiology Research Template

Target Disease

Research Objectives

Required Information

1. Core Pathophysiology

2. Key Molecular Players

3. Biological Processes (for GO annotation)

4. Cellular Components

5. Disease Progression

6. Phenotypic Manifestations

Citation Requirements

Output Format