DeCure for Carbamoyl phosphate synthetase I deficiency disease
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for carbamoyl phosphate synthetase I deficiency disease — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCarbamoyl phosphate synthetase I deficiency disease maps to a 2-gene Open Targets module — the target space DeCure's AI scientist screens approved drugs against.
DeCure.ai methodSignature reversal (LINCS) plus network proximity (STRING) rank already-approved drugs likely to perturb this module — the same engine that produces DeCure.ai's repurposing hypotheses.
Repurposing thesisScreening approved medicines against this disease module, then publishing the evidence for the strongest candidate. Known pharmacology and human exposure data make the first question sharper — they do not establish safety or efficacy in a new indication.
Research record
01
ResearchComing soon
Candidate research + dossier — target rationale, drug-repurposing thesis and evidence pack.proof: Published dossier + on-chain hash
02
ValidationComing soon
In-vitro biological validation at a contract research org (CRO).proof: CRO contract + in-vitro report
03
Peer review & paperComing soon
Peer-reviewed paper published open-access (preprint + journal).proof: DOI + open-access link + on-chain hash
Current lead
No approved-drug candidate for carbamoyl phosphate synthetase i deficiency disease is corroborated in the literature DeepSearch retrieved. Some conditions are managed with non-pharmacological care — a device, surgery or physical therapy — rather than a medicine; that may be the case here, or the literature we found may simply be too sparse yet to support a drug-repurposing angle.
Molecular view
carbamoyl-phosphate synthase 1 (CPS1) — CPS1 is one of the genes genetically linked to this disease in Open Targets — shown as context, not as a drug target we're pursuing: no approved-drug candidate for this disease is yet corroborated in the literature we found.
Loading structure…
helix sheet 4-fluorophenyldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6UEL · 1.9 Å · ligand N~1~-[(4-fluorophenyl)methyl]-N~1~-methyl-N~4~-(4-methyl-1,3-thiazol-2-yl)piperidine-1,4-dicarboxamide (Q5A). Experimental structure, not a prediction.
What the evidence adds up to
Carbamoyl phosphate synthetase I deficiency can present with neonatal onset of symptoms. In one 1977 case, a boy developed hypotonia and hypothermia 48 hours after birth, followed by pulmonary haemorrhage, melaena and haematemesis; he died on the fifth day despite ventilatory assistance and peritoneal dialysis. Post-mortem tissue analysis showed virtual absence of carbamoyl phosphate synthetase I activity, with other urea cycle enzymes normal. A 2018 report describes a neonate with hyperammonaemia, increased plasma alanine, and decreased serum citrulline, found by next-generation sequencing to carry compound heterozygous CPS1 mutations (c.1631C>T and c.1981G>T) inherited from each parent.
Not all cases are fatal in the newborn period. A 1981 report describes two teen-age sisters with carbamoyl phosphate synthetase I deficiency whose cognitive function, measured by psychometric tests, fell in the borderline range. The authors note that survivors of the neonatal period are not necessarily severely mentally retarded, contrary to earlier emphasis. A 1993 commentary highlights a late clinical presentation in a patient with partial deficiency, pointing out that genetic diseases are not as rare as often assumed and that inborn errors of metabolism illustrate heterogeneity and variability.
Mutational analysis in three Japanese patients, reported in 2004, identified compound heterozygous mutations in the CPS1 gene: 3422T/G (V1141G) plus 3784C/T (R1262X), 1528delG plus 2752T/C (S918P), and 2549G/A (R850H) plus 2797delT (L933X). In one patient, the 2797delT mutation was not detected in cDNA from biopsied liver, suggesting absent or very low mRNA expression from that allele. The 2018 study notes that its finding expands the spectrum of CPS1 mutations associated with the deficiency.
What is still missing are systematic data on long-term outcomes beyond small case series, prospective studies that stratify patients by residual enzyme activity or genotype, and funding for newborn screening programmes that could identify partial deficiencies before crisis. No controlled trials of any treatment are reported in these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Acta Paediatrica · 1977 · 14 citations
CARBAMYL‐PHOSPHATE‐SYNTHETASE DEFICIENCY WITH NEONATAL ONSET OF SYMPTOMS
AbstractThe clinical course and biochemical findings in a case of carbamyl-phosphate-synthetase deficiency are described. The patient, a boy, presented 48 h after birth with rapidly developing hypotonia and hypothermia. Pulmonary haemorrhage, melaena and haematemesis ensued and despite ventilatory assistance and peritoneal dialysis the patient died on the fifth day. A virtual absence of carbamyl phosphate synthetase I (N-acetylglutamate dependent) was proved by analysis of tissue samples removed post mortem. Other urea cycle enzymes were normal.
Journal of Inherited Metabolic Disease · 2004 · 12 citations
Mutational analysis of carbamoylphosphate synthetase I deficiency in three Japanese patients
AbstractWe describe the results of mutational analysis of the carbamoylphosphate synthetase I (CPSI) gene in three nonconsanguineous patients with CPSI deficiency. Compound heterozygotes of 3422T/G (V1141G) plus 3784C/T (R1262X), 1528delG (510-514 ARQLX) plus 2752T/C (S918P), and 2549G/A (R850H) plus 2797delT (L933X) were identified through genomic analysis; however, the 2797delT (L933X) mutation was not detected in cDNA analysis using biopsied liver, suggesting that mRNA expression rom this mutant allele is absent or markedly low.
Journal of Pediatric Psychology · 1981 · 6 citations
Cognitive Functioning in Two Sisters with Carbamyl Phosphate Synthetase I Deficiency
AbstractThe case histories of two teen-age girls with carbamyl phosphate synthetase I deficiency are presented. Appropriate psychometric studies show that these women are functioning in the borderline range of cognitive skills. These results emphasize that individuals with Krebs-Henseleit urea cycle enzyme deficiencies who survive the neonatal period are not necessarily severely mentally retarded as has been stressed previously.
Archives of Pediatrics and Adolescent Medicine · 1993 · 3 citations
Heterogeneity and Variability of Inborn Errors of Metabolism
AbstractThe article by Lo et al<sup>1</sup>in this issue, describing a late clinical presentation in a patient with partial carbamyl phosphate synthetase I deficiency, highlights a common diagnostic pitfall. The usual thinking of the medical community is that genetic diseases are so rare that we are not going to see them, and when we do see them there is nothing we can do about them. Both of these misconceptions turn out to be wrong. As many as 5% of newborns will express a significant genetic disorder during infancy and childhood, and at least a similar if not larger percentage may express a genetic disorder at a somewhat later stage of life. The group of inborn errors of metabolism (errors of the urea cycle, amino acid metabolism, and organic acid metabolism) represents one of the better examples for the two major concepts of human genetics—heterogeneity and
Journal of Pediatric Endocrinology and Metabolism · 2020 · 2 citations
ATP synthase deficiency due to m.8528T>C mutation – a novel cause of severe neonatal hyperammonemia requiring hemodialysis
AbstractOBJECTIVES: Hyperammonemia in a newborn is a serious condition, which requires prompt intervention as it can lead to severe neurological impairment and death if left untreated. The most common causes of hyperammonemia in a newborn are acute liver failure and inherited metabolic disorders. Several mitochondrial disorders have been described as a cause of severe neonatal hyperammonemia. CASE PRESENTATION: Here we describe a new case of adenosine-triphosphate (ATP) synthase deficiency due to m.8528T>C mutation as a novel cause of severe neonatal hyperammonemia. So far six patients with this mutation have been described but none of them was reported to need hemodialysis in the first days of life. CONCLUSION: This broadens the so far known differential diagnosis of severe neonatal hyperammonemia requiring hemodialysis.
[Detection of CPS1 gene mutation in a neonate with carbamoyl phosphate synthetase I deficiency].
AbstractOBJECTIVE: To explore the genetic basis for a neonate featuring hyperammonemia. METHODS: The patient was examined and tested by tandem mass spectrometry and next generation sequencing (NGS). Suspected mutations were confirmed by Sanger sequencing of the proband and her parents. Potential impact of the mutation was predicted with SIFT, PolyPhen-2 and MutationTaste software. RESULTS: Plasma ammonia and alanine were significantly increased in the proband, while serum citrulline was decreased. The neonate was found to harbor compound heterozygous mutations of the CPS1 gene [c.1631C>T(p.T544M) and c.1981G>T(p.G661C)], which were respectively inherited from her father and mother. CONCLUSION: The carbamoyl phosphate synthetase I deficiency of the proband can probably be attributed to the mutations of the CPS1 gene. Above finding has expanded the spectrum of CPS1 mutations in association with carbamoyl phosphate synthetase I deficiency.
Disease module: DeepOracle (Open Targets). Structures: RDKit from PubChem SMILES. Literature: retrieved by DeepSearch across 234,678,978 indexed works (targeted per-candidate search), resolved on OpenAlex.
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