DeCure for Neonatal intrahepatic cholestasis due to citrin deficiency
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for neonatal intrahepatic cholestasis due to citrin deficiency — screening already-approved drugs against its 1-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleNeonatal intrahepatic cholestasis due to citrin deficiency maps to a 1-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 neonatal intrahepatic cholestasis due to citrin deficiency 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
solute carrier family 25 member 13 (SLC25A13) — SLC25A13 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 apo structuredrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4P5W · 2.4 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
In a Korean series of six citrin deficiency cases, four infants with neonatal intrahepatic cholestasis due to citrin deficiency (NICCD) had high citrulline on newborn screening or neonatal cholestasis, with conjugated hyperbilirubinemia, elevated liver enzymes, hypoalbuminaemia, mild hyperammonaemia, and elevated citrulline, methionine and threonine. All four resolved spontaneously between 5 and 9 months of age. Two adult men presented with sudden loss of consciousness, hyperammonaemia and citrullinaemia. A Chinese female NICCD patient with two novel truncating mutations had extreme aminoacidaemia, coagulation disorders and myocardial damage, the latter attributed to hyperbilirubinaemia and bile acids. A Polish infant with NICCD had low birth weight, failure to thrive, prolonged cholestatic jaundice with coagulopathy and hypoalbuminaemia; normal newborn tandem mass spectrometry screening was followed by high blood citrulline at three months, and unreported findings included N-hypoglycosylation and increased serum very-long-chain fatty acids, probably secondary to liver impairment.
A retrospective analysis of 61 confirmed NICCD cases from a Chinese tertiary centre compared 52 survivors without transplant against 9 deceased patients. Mean age at referral was higher in the mortality group (9.58 vs 3.96 months, p < 0.000). Infection was more frequent in those who died (p = 0.023). Among the deceased, 44.4% had not received lactose-free and/or medium-chain-triglyceride-enriched (LF/MCT) formula, versus 9.6% of survivors (p = 0.021). Lower platelet count, lower gamma-glutamyl transpeptidase, lower total cholesterol, lower blood citrulline, and higher blood ammonia and tyrosine were all significantly associated with death. The authors concluded that late referral, infection, delayed LF/MCT formula use, lower platelet count, lower GGT and total cholesterol, lower citrulline, and higher ammonia and tyrosine were associated with poor prognosis.
No drug treatment is described in any of these abstracts. The only intervention associated with better survival is dietary: lactose-free and/or MCT-enriched formula. What remains missing is prospective trial data on any pharmacological therapy, standardised protocols for when to start and stop the special formula, and systematic stratification of patients by mutation type, age at referral, and presence of infection. The natural history of spontaneous resolution in some infants contrasts with fatal outcomes in others, but no molecular or clinical predictor reliably distinguishes them at diagnosis.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
International Journal of Molecular Medicine · 2007 · 28 citations · open access
Six cases of citrin deficiency in Korea
AbstractCitrin deficiency resulting from mutations of the SLC25A13 gene is associated with two major clinical phenotypes; neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and adult-onset type 2 citrullinemia (CTLN2). In Korea, 6 cases of citrin deficiency were diagnosed based on biochemical and molecular findings. Four NICCD patients (2 boys and 2 girls) presented high citrulline levels on a newborn screening test or neonatal cholestasis. They were associated with conjugated hyperbilirubinemia, elevated liver enzymes, hypoalbuminemia, mild hyperammonemia, elevated citrulline, methionine and threonine. All of the hepatic manifestations were resolved spontaneously at the age of 5-9 months. Mutation analysis identified them as compound heterozygotes carrying each of the c.851del4, IVS11+1G>A, IVS13+1G>A, G393S, and IVS16ins3kb mutant alleles. Two adult male CTLN2 patients were identified. They were aged 24 and 37 years, and presented sudden loss of consciousness, hyperammonemia and citrullinemia. They were compound heterozygotes with IVS13+1G>A and IVS16ins3kb, and with c.851del4 and IVS11+1G>A mutant alleles. This report describes the clinical characteristics, biochemical findings and molecular analysis of the SLC25A13 gene of patients with citrin deficiency in Korea.
World Journal of Gastroenterology · 2015 · 22 citations · open access
Citrin deficiency presenting as acute liver failure in an eight-month-old infant
AbstractCitrin deficiency typically presents as neonatal intrahepatic cholestasis and resolves in late infancy. Here we report a case of citrin deficiency that presented as acute liver failure in late infancy in an apparently healthy child. The full-term male infant weighed 3400 g at birth, and exhibited normal development for eight months, at which time he contracted bronchial pneumonia. The infant developed jaundice and laboratory tests indicated elevated bilirubin and ammonia levels and an abnormal coagulation profile. Plasma amino acid analysis showed elevated levels of tyrosine, methionine, citrulline, and arginine. Citrin deficiency was suspected, and genomic DNA analysis revealed a mutation (IVS16ins3kb) in SLC25A13, which encodes a mitochondrial aspartate-glutamate carrier protein. The infant was immediately put on a lactose-free, medium-chain-triglyceride-enriched formula with ursodeoxycholic acid and lipid-soluble vitamins. However, cholestasis and abnormal laboratory indices persisted, and the infant died at the age of 11.5 mo, two days before a scheduled liver transplantation. This case demonstrates that citrin deficiency can present in late infancy as acute liver failure triggered by infection, and may require liver transplantation.
Journal of Pediatric Endocrinology and Metabolism · 2014 · 10 citations
Novel mutations in the SLC25A13 gene in a patient with NICCD and severe manifestations
AbstractNeonatal intrahepatic cholestatic due to citrin deficiency (NICCD) is an autosomal recessive disorder caused by mutations in the SLC25A13 gene and characterized by neonatal/infantile-onset cholestatic hepatitis syndrome associated with conjugated hyperbilirubinemia and multiple aminoacidemias. We report the case of a Chinese female patient with NICCD disease who manifested prominent clinical features. The patient was diagnosed with NICCD based on cholestasis, aminoacidemia, and hypoproteinemia. She exhibited extreme aminoacidemia, coagulation disorders and untypical myocardial damage, which are rare in other NICCD patients genetically confirmed by us. This myocardial damage observed in obstructive jaundice could be caused by both hyperbilirubinemia and redundant blood bile acids. Screening the SLC25A13 gene revealed that this patient was compound heterozygous harboring two novel mutations, the c. 640C>T (p. Gln214X) in exon 7 and the c. 1709_1710insA (p. Ile570fs573X) in exon 16. Both mutations cause a premature stop codon and thereby truncated peptide or nonsense-mediated with loss of natural function accordingly. In conclusion, extremely manifested clinical features, including significant hyperbilirubinemia, multiple aminoacidemia, hypoproteinemia, coagulation disorders, and myocardial damage related to redundant blood bilirubin and bile acids, were observed in a NICCD patients with two novel mutations.
Neonatal cholestasis due to citrin deficiency: diagnostic pitfalls
AbstractCitrin deficiency can manifest in newborns or infants as neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD). The paper presents a case of Polish NICCD patient presenting with low birth weight, failure to thrive, prolonged cholestatic jaundice with coagulopathy and hypoalbuminemia with normal results of MS/MS newborn screening but with high blood citrulline level observed at 3 months of age. Unreported findings included N-hypoglycosylation and increased serum very-long-chain fatty acids (VLCFA), probably secondary to liver impairment. Final diagnosis was established based on whole-exome sequencing (WES) analysis.
Risk factors associated with mortality in neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) and clinical implications
AbstractAbstract Background Neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD) has high prevalence in East Asia, and has been reported in other parts of the world. NICCD is also the most common form of genetic cholestasis among East Asians. There has been reports of mortalities or liver transplants associated with NICCD, but risk factors associated with poor outcome were unknown. Our objective is to report NICCD mortalities in a tertiary pediatric hepatology center, and to explore associated risk factors along with implications to clinical practice. Method This is a retrospective analysis of NICCD cases collected from June 2003 until January 2017 in the Children’s Hospital of Fudan University. Clinical, biochemical, and genetic data were compared between deceased cases and survivors without liver transplant. Results Sixty-one confirmed NICCD cases, including 52 cases in the survival group, and 9 cases in the mortality group, were included in the analysis. Mean age at referral in the mortality group was significantly higher when compared to the survival group (9.58 ± 5.03 VS 3.96 ± 3.13 months, p < 0.000). The proportion with infection in the mortality group was significantly higher than the survival group (p = 0.023). 44.4% of patients in the mortality group did not receive lactose-free and/or medium chain triglycerides enriched (LF/MCT) formula, and this percentage was significantly higher than the survival group (9.6%, p = 0.021). Mean platelet (PLT) count in the mortality group was significantly lower than the survival group (p = 0.010). Mean serum gamma-glutamyl transpeptidase (GGT), and total cholesterol (TCH) levels were significantly lower in the mortality group when compared to the survival group with p values of 0.001, and 0.019, respectively. Those who died had higher serum ammonium levels than survivors (p = 0.016). Mean level of citrulline was significantly lower in the mortality group compared to the survival group (p = 0.010). On the other hand, mean level of tyrosine was significantly higher in the mortality group than that of the survival group (p = 0.015). Conclusion Late referral, presence of infection, delayed treatment with LF/MCT formula, lower platelet count, lower levels of GGT, total cholesterol, blood citrulline, and higher level of blood ammonia and tyrosine, were associated with poor prognosis in NICCD.
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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