DeCure for Congenital bile acid synthesis defect 4
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for congenital bile acid synthesis defect 4 — 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 moduleCongenital bile acid synthesis defect 4 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 congenital bile acid synthesis defect 4 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.
What the evidence adds up to
Congenital bile acid synthesis defect type 1 (CBAS1) is caused by mutations in the HSD3B7 gene, which encodes the enzyme 3β-hydroxy-Δ5-C27-steroid dehydrogenase. Around 100 cases have been identified worldwide. In a 2015 report, an infant presenting with neonatal cholestasis, normal γ-glutamyltransferase (24 U/L) and low total bile acids (2.2 μmol/L) was found to carry two novel compound heterozygous HSD3B7 mutations: c.503G>A (p.Trp168Ter) and c.683G>A (p.Arg228Gln). The first introduces a premature stop codon; the second was predicted damaging by both SIFT (score 0.05) and PolyPhen-2 (score 1). The patient also carried a single SLC25A13 mutation but did not develop citrin deficiency. After initial treatment with ursodeoxycholic acid (62.5 mg twice daily), liver function improved modestly (ALT fell from 174 to 34 U/L, TBIL from 106.0 to 93.6 μmol/L). Treatment was switched to chenodeoxycholic acid (41.66 mg twice daily) after discharge, and at two-week telephone follow-up jaundice had resolved and aminotransferases normalised.
A 2025 case report describes a 4-year-old child presenting with splenomegaly, fever, lymphadenopathy and mild cholestasis without hepatomegaly, with a history of recurrent infections since age 3. After extensive negative work-up, next-generation sequencing identified a previously unreported homozygous HSD3B7 variant, and abnormal urinary bile acid metabolites were found. Bile acid replacement therapy reversed the cholestasis. The authors note that early diagnosis and treatment with cholic acid are considered crucial to reverse hepatopathy and prevent fatal outcomes, but also emphasise that the non-specific presentation makes diagnosis challenging. A separate 2025 case series of three first-degree relatives with congenital bile acid synthesis defect type 2 (AKR1D1 deficiency) reported significant clinical improvement after starting cholic acid.
Ursodeoxycholic acid is described as having limited benefit in CBAS1; it does not reduce harmful intermediate metabolites in urine and may cause liver damage. Cholic acid is considered safer than chenodeoxycholic acid, which may be toxic to liver cells at late disease stages. One 2018 review states that oral cholic acid is a safe and effective therapy for the most common defects, but that untreated disease may lead to early cirrhosis and liver failure. A 1983 summary notes that the relationship between abnormal bile acid production and disease pathogenesis remains unknown, and that more studies are needed.
What is still missing: prospective trials comparing cholic acid against chenodeoxycholic acid in CBAS1, standardised diagnostic protocols for centres without mass spectrometry, long-term outcome data beyond telephone follow-up, and systematic screening of neonatal cholestasis cohorts to determine the true prevalence of these mutations.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Chinese Medical Journal · 2015 · 19 citations · open access
Novel Mutations in the 3β-hydroxy-Δ5-C27-steroid Dehydrogenase Gene (HSD3B7) in a Patient with Neonatal Cholestasis
AbstractBile acid synthetic defect (BASD) is a rare category of genetic disorders that are responsible for approximately 2% of persistent cholestasis in infants.[1] Until date, four enzymes responsible for congenital defects of bile acid synthesis (CBAS) have been identified. 3β-hydroxy-[INCREMENT]5-C27-steroid dehydrogenase (3β-HSD), the deficiency of which can cause CBAS1 (OMIM No. 607765), is encoded by the gene HSD3B7 and works in the second step of transforming the steroid into primary bile acids. An infant (1 month and 9-day-old) was brought to our hospital by her parents with an indication of lasting jaundice. The baby had been delivered by spontaneous vaginal delivery without complications at the full-term gestation week, weighing 3300 g. Jaundice had appeared just 2 days after birth and persisted after 8 days. Her temperature at that time was normal, the stool sample had a light yellow color, and there was no sign of diarrhea or steatorrhea. After 3 days of treatment in another hospital, the patient was referred to our hospital because of hyperbilirubinemia and liver dysfunction. Initial physical examination on admission showed hepatomegaly (about 4 cm below the rib) and obvious jaundice. After admission, we conducted a thorough examination to determine the cause for cholestasis. The ultrasound scan indicated no particular sign of intrahepatic or extrahepatic bile duct malformation or obstruction. Tests for conventional pathogens in infants had no significant positive findings; these were as follows: Anti-Cytomegalovirus (CMV), anti-Rubella virus, and anti-Herpes simplex virus (HSV) I: IgM−, IgG+; anti-Toxoplasma gondii and anti-HSV II: IgM−, IgG−; anti-Parvovirus B19: IgM−; shell viral assay for urine human CMV detection: –; blood Epstein–Barr virus DNA: –; hepatitis A, B, C, and E virus antibodies: –; human immunodeficiency virus antibody: –; and syphilis antibody: –. Urine sample analysis by gas chromatography-mass spectrometry (GC-MS) ruled out several organic acidurias. Blood sample acylcarnitine and amino acid profiles did not support the diagnosis of fatty acid or amino acid metabolic diseases. Peculiarly, in spite of high aminotransferase (alanine aminotransferase [ALT] 174 U/L, aspartate aminotransferase [AST] 195 U/L) and bilirubin (total bilirubin [TBIL] 106.0 μmol/L, direct bilirubin [DBIL] 78.30 μmol/L) levels, the patient had normal γ-glutamyltransferase (GGT, 24 U/L) and total bile acid (2.2 μmol/L) concentrations, which led us to consider the possibility of BASD. With the parents’ consent, we ran a genetic test of the patient and her parents for a set of genes responsible for neonatal cholestasis. The potential influence of the detected mutations on protein function was estimated using Sorting Intolerant from Tolerant (SIFT) (http://sift.jcvi.org/www/SIFT_BLink_submit.html) and PolyPhen-2 (http://genetics.bwh.harvard.edu/pph2/) software. Two compound heterozygous HSD3B7 gene mutations and a single SLC25A13 gene mutation were identified in the patient. Sequencing of the patient and parental homologous regions revealed the maternally inherited mutation c.503G>A (p.Trp168Ter) and the paternally inherited mutation c.683G>A (p.Arg228Gln) [Figure 1]. The SLC25A13 mutation c.852-855delTATG (p.Met285fs) was inherited from her mother, but the allele gene was normal.Figure 1: Sequence analysis of exons of the HSD3B7 gene of the patient. Two identified mutations were c.503G>A (p.Trp168Ter) in exon 5 and c.683G>A (p.Arg228Gln) mutation in exon 6. The patient inherited the aforementioned two mutations from her parents as the compound heterozygote. The nucleotide exchange and insertion are marked by arrows.The c.503G>A (p.Trp168Ter) mutation in exon 5 causes an abrupt termination of 3β-HSD transcription. The c.683G>A (p.Arg228Gln) mutation in exon 6 was predicated to have a probable damaging influence on protein function (PolyPhen score 1; SIFT score 0.05). Both HSD3B7 mutations mentioned above have not been identified either in 100 normal subjects studied by us or in Chinese members of the 1000 Genomes Project and other human populations. The SLC25A13 mutation causes neonatal intrahepatic cholestasis due to citrin deficiency (NICCD; MIM No. 605814). The patient inherited the SLC25A13 mutation from her mother and a normal SLC25A13 gene from her father, so she had no aminoacidemia, which is typical for NICCD. The patient's genetic results ultimately led to the diagnosis of CBAS1; however, the parents declined our proposal of liver biopsy. Ursodeoxycholic acid (UDCA) treatment (62.5 mg, b.i.d) had been initiated on the 2nd day of admission to relieve her clinical symptoms. After the establishment of CBAS1 diagnosis, we planned to switch to chenodeoxycholic acid (CDCA) treatment, but the parents demanded an early discharge and received CDCA treatment (41.66 mg, b.i.d) at another hospital. By the time of discharge from our hospital, the patient showed an improvement of liver function (ALT: 34 U/L, AST: 143 U/L, TBIL: 93.6 μmol/L, DBIL: 78.00 μmol/L; decreased aminotransferase and bilirubin; increased albumin, prealbumin, and globulin). At follow-up 2 weeks later by telephone, the parents informed that jaundice had completely faded, and the aminotransferase level had returned to normal. CBAS1 due to HSD3B7 mutations often has an early onset; in rare cases, adults with liver dysfunction turn out to be 3β-HSD deficient. 3β-HSD enzyme dysfunction can lead to bile acid biosynthesis errors, which will cause primary bile acid (cholic acid [CA] and CDCAs) deficiency and atypical bile acid and sterol accumulation. Lack of primary bile acids results in bile acid flow reduction, which in turn leads to fat and fat-soluble vitamin malabsorption. The atypical metabolites can be toxic to liver cells, resulting in liver dysfunction. Although the clinical manifestations in patients (including cholestasis, bleeding tendency, rickets, failure to thrive, etc.)[2] are varied, the GGT and total bile acid concentrations are usually within normal range.[3] Liver biopsy often shows giant cell hepatitis, and at late stages, bridging fibrosis and micronodular cirrhosis can also be seen.[2] Bile acid analysis of serum and urine using GC-MS or fast atom bombardment MS (FAB-MS) is a conventional way to screen BASD, but this test is currently not available in China. CDCA or CA treatments have been recommended by some doctors on the basis of clinical data, where patients who received treatment at an early age remained asymptomatic for many years and could develop normally. CA seems to be a better choice than CDCA, because, at late disease stages, CDCA may have toxic effects on hepatic cells.[3] Gonzales et al. investigated the long-term effect of oral CA for hereditary defects of primary bile acid synthesis and suggested it was safe and effective for 3β-HSD-deficient patients.[4] UDCA treatment can have limited benefits, but it has little effect in reducing the harmful intermediate metabolites in urine[5] and can even cause liver damage. Our patient was admitted for cholestasis, the common causes of which had been excluded after a thorough examination. Her GGT and total bile acid levels stayed normal after admission, which reminded us of BASD. Because serum and urine bile acid analyses by GC-MS and FAB-MS were not available, we tested for cholestasis-related gene mutations instead. We identified two novel HSD3B7 gene mutations in our patient, which could be a new underlying pathogenesis of 3β-HSD deficiency. BASD accounts for about 2% of neonatal cholestasis cases, and early primary bile acid replacement treatment can achieve good results.[5] For cholestasis with normal GGT and total bile acid concentrations, the possibility of BASD should be considered and confirmed with genetic testing. Even though initial UDCA treatment can have some beneficial effects, it is important to investigate further instead of immediately concluding a diagnosis of idiopathic cholestasis. Once confirmed, the UDCA must be stopped immediately and be replaced with primary bile acids. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
Journal of Pediatric Gastroenterology and Nutrition · 1983 · 3 citations
Neonatal Cholestatic Syndromes Associated with Alterations in Bile Acid Synthesis
AbstractIn summary, the conditions discussed above are examples of diseases that result in deficient bile acid synthesis and production of abnormal bile acids. Although the relationship between the production of these abnormal bile acids and the pathogenesis of these diseases remains unknown, they continue to provide us with a better understanding of normal pathways of bile acid production. Clearly, more studies are needed before these interesting metabolic defects and normal infantile bile acid metabolism itself are well understood.
Clinical Medicine Insights Pediatrics · 2025 · 1 citations · open access
The Diagnostic Saga of a Rare Congenital Bile Acid Synthesis Disorder: A Case Report
AbstractCongenital bile acid synthesis disorder type 1 is an extremely rare disease with around 100 cases identified worldwide. Diagnosis remains challenging for pediatricians in view of the non-specific, variable clinical presentations of cholestasis, fat malabsorption, and liver cirrhosis. Early diagnosis and therapy with cholic acid are crucial to reverse the hepatopathy and prevent fatal outcomes. This paper sheds light on the diagnostic challenges of congenital bile acid synthesis disorder type 1 in a patient with an unusual presentation and a previously unreported mutation in the HSD3B7 gene. Moreover, this report aims to increase awareness of this treatable disorder among pediatricians. A 4-year-old child presented to our Medical Center with splenomegaly, fever, multiple lymphadenopathies, and mild cholestasis without hepatomegaly. History was remarkable for recurrent infections since the age of 3 years. Differential diagnosis included viral infections, malignancies, and inherited metabolic disorders. After an extensive negative work-up, genetic testing by next-generation sequencing identified a previously unreported homozygous disease-causing variant in the HSD3B7 gene, confirming the diagnosis of congenital bile acid synthesis disorder type 1. Suggestive abnormal urinary bile acids metabolites were also identified. Bile acid replacement therapy was initiated with reversal of cholestasis. This case highlights an unusual phenotypic presentation and the diagnostic challenges of an extremely rare disorder of bile acid synthesis. An increased awareness among pediatricians and the use of next-generation sequencing as a first-tier test in the setting of non-specific clinical presentations may shortcut the list of extensive investigations, allowing an early diagnosis of such treatable disorders, thus improving the patients' outcomes.
Varied phenotypic presentation of congenital bile acid synthesis defect type 2 in a set of first-degree relatives with the same genetic mutation
AbstractBile acid synthesis disorders represent a rare subset of cholestatic conditions that, if unrecognised, may progress to end-stage liver disease requiring transplantation. These disorders result from deficiencies in one of the 17 enzymes involved in the conversion of cholesterol into primary bile acids. We present a case series of three first-degree relatives diagnosed with congenital bile acid synthesis defect type 2 (AKR1D1 deficiency), a disorder characterised by impaired steroid 5β-reductase activity. After initiating cholic acid, all patients demonstrated significant clinical improvement.
Institutional Research Information System University of Ferrara (University of Ferrara) · 2018 · 0 citations
L’acido colico nel trattamento degli errori congeniti del metabolismo degli acidi biliari
AbstractInborn errors of primary bile acid synthesis are rare genetic disorders that cause chronic liver disease, steatorrhea and fat-soluble vitamins deficiency in childhood. Absence of itching, normal γGT and serum bile acids suggest the diagnosis, confirmed by urinary mass spectrometry and gene analysis. Oral cholic acid is a safe and effective therapy for the most common defects that if untreated may lead to early cirrhosis and \nliver failure.
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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