DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for holocarboxylase synthetase 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 moduleHolocarboxylase synthetase 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
approvedBiotinApproved drug
Structures already discussed alongside holocarboxylase synthetase deficiency in the retrieved literature, rendered from public PubChem SMILES. Which drugs appear here reflects the evidence found, not a ranked prediction.
What the evidence adds up to
Holocarboxylase synthetase deficiency is a rare autosomal recessive disorder of biotin metabolism. In a 1996 study of nine patients, six different point mutations in the HLCS gene were identified, with four clustering in the putative biotin-binding domain. A 2002 report of four patients (two Italian, one Iranian, one Australian) found six mutations, including the first homozygous case of the L216R mutation in the N-terminal region; that patient had a severe clinical phenotype and only partial responsiveness to biotin, suggesting a genotype–phenotype correlation. The same L216R homozygous variant was later reported in a 2025 case of a Polynesian neonate who developed cholestatic liver disease, only the second such case described, again pointing to a possible link between that mutation and liver involvement.
A 2024 case report described an 8-day-old female neonate with severe lactic acidosis and compound heterozygous HLCS variants (c.710T>C p.Leu237Pro and c.1544G>A p.Ser515Asn). After receiving biotin mega-dose therapy (10 mg/day), lactic acidosis improved dramatically the next day, and mechanical ventilation was discontinued within six days. The patient showed normal growth and development with stable laboratory findings up to 18 months of age. The 2002 study, however, documented variable responses to biotin treatment among its four patients, with the homozygous L216R patient showing only partial responsiveness, indicating that not all genotypes respond equally well.
What remains missing is systematic data on long-term outcomes across a larger cohort of patients with different HLCS mutations. No controlled trial has compared biotin doses or schedules. The genotype–phenotype correlations suggested by these small case series need confirmation in a larger, prospectively followed population. Patient stratification by specific mutation, particularly the L216R variant, may be necessary to predict response, but funding for such studies in this ultra-rare disease is limited.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Human Molecular Genetics · 1996 · 60 citations
Clustering of mutations in the biotin-binding region of holocarboxylase synthetase in biotin-responsive multiple carboxylase deficiency
AbstractHolocarboxylase synthetase (HCS) catalyses the biotinylation of the four biotin-dependent carboxylases found in humans. A deficiency in HCS results in biotin-responsive multiple carboxylase deficiency (MCD). We have identified six different point mutations in the HCS gene in nine patients with MCD. Two of the mutations are frequent among the MCD patients analyzed. Four of the mutations cluster in the putative biotin-binding domain as deduced from the corresponding Escherichia coli enzyme and consistent with an explanation for biotin-responsiveness based on altered affinity for biotin. The two others may define an additional domain involved in biotin-binding or biotin-mediated stabilization of the protein.
American Journal of Medical Genetics · 2002 · 40 citations
Clinical findings and biochemical and molecular analysis of four patients with holocarboxylase synthetase deficiency
AbstractHolocarboxylase synthetase (HLCS) deficiency (HLCSD) is a rare autosomal recessive disorder of biotin metabolism. HLCS catalyzes the biotinylation of the four human biotin-dependent carboxylases. Using the newly available human genomic sequence, we report the map of HLCS genomic structure and the predicted exon/intron boundaries. Moreover, the molecular studies of four patients (two Italians, one Iranian, and one Australian) affected by HLCS deficiency are here reported. The clinical findings, the age of onset, and response to biotin treatment differed between our patients. The diagnosis was made by organic acid analysis and confirmed by enzymatic analysis in three patients. Six mutations in the HLCS gene were identified, including two novel (N511K and G582R) and four known missense mutations (L216R, R508W, V550M, and G581S). Five of the mutations are localized within the HLCS biotin-binding domain, whereas the L216R amino acid change is located in the N-terminal region outside of the putative biotin-binding domain. This mutation, previously reported in a heterozygous state, was detected for the first time in a patient with homozygous status. The patient's severe clinical phenotype and partial responsiveness to biotin support a genotype-phenotype correlation through the involvement of residues of the N-terminal region in a substrate specificity recognition or regulation of the HLCS enzyme.
Molecular Genetics & Genomic Medicine · 2024 · 2 citations · open access
Dramatic Clinical Improvement With Biotin Mega‐Dose Therapy in a Neonate With Holocarboxylase Synthetase Deficiency
AbstractINTRODUCTION: Holocarboxylase synthetase deficiency (HLCS deficiency, OMIM #253270) is an exceedingly rare metabolic disorder resulting in multiple carboxylase deficiencies owing to impaired biotin cycle. Clinical manifestations include severe metabolic acidosis, hyperammonemia, tachypnea, skin rash, alopecia, feeding problems, hypotonia, developmental delay, seizures, and, in severe cases, death. METHODS AND RESULTS: An 8-day-old female neonate presented with severe lactic acidosis, necessitating sedation and mechanical ventilation. Despite receiving supportive care, no evident clinical improvement was observed, accompanied by the onset of generalized ichthyosis. Genetic analysis of actionable metabolic disorders revealed compound heterozygous variants of HLCS (NM_000411.8), specifically c.[710T>C (p.Leu237Pro)]; [1544G>A (p.Ser515Asn)], prompting the initiation of biotin mega-dose therapy (10 mg/day). Remarkably, dramatic clinical improvement in lactic acidosis was observed the day after initiating biotin administration, leading to the discontinuation of mechanical ventilation within 6 days. The patient remained in stable condition during follow-up, exhibiting normal growth and development along with consistently stable laboratory findings up to 18 months of age. CONCLUSION: Our case highlights the significance of early genetic testing in neonates with unexplained metabolic disorders to enable timely diagnosis and therapy initiation. Biotin therapy has demonstrated remarkable efficacy in improving the clinical condition of patients with HLCS deficiency, leading to favorable outcomes.
Holocarboxylase Synthetase Deficiency: A Second Case Report With Neonatal Cholestatic Liver Disease
AbstractABSTRACT Holocarboxylase synthetase deficiency is an autosomal recessive inborn error of metabolism characterised by life‐threatening metabolic acidosis, ketoacidosis and hyperammonaemia through reduced biotin‐dependent carboxylase activity. We report the presentation of a Polynesian neonate with severe metabolic acidosis secondary to holocarboxylase synthetase deficiency with the development of cholestatic liver disease thought to be secondary to holocarboxylase synthetase deficiency. This is only the second reported case of holocarboxylase synthetase deficiency associated with cholestatic liver disease. Both of these cases were a result of the same homozygous c.647T>G L216R pathogenic variants in the HLCS gene suggesting a possible genotype–phenotype correlation and broadening the phenotypic understanding of this disease.
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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