DeCure for Intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome — screening already-approved drugs against its 3-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleIntellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome maps to a 3-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 intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome 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
In a study of 11 patients with de novo STXBP1 mutations from the Deciphering Developmental Disorders project, six carried missense variants. Pathogenic missense mutations were significantly more likely than population variants to occur at highly conserved positions and to be buried inside the protein domain, and they were more likely to destabilise the domain structure, increasing the proportion of partially unfolded domains prone to aggregation or degradation. No genotype–phenotype correlation was detected. Unlike previously reported cases, most of these DDD patients did not present with very early-onset or severe epilepsy and encephalopathy, though all had developmental delay with intellectual disability, most displayed behavioural problems, and some suffered seizures in later childhood. The authors concluded that loss-of-function variants across STXBP1 can cause severe intellectual disability with or without seizures, consistent with a haploinsufficiency mechanism, and that the presence or absence of early seizures may reflect ascertainment bias.
A separate review of the Aristaless-related homeobox (ARX) gene, one of the most frequently mutated X-linked intellectual disability genes after FMR1 and MECP2, reported that more than 110 mutations had been described. The phenotype always involves intellectual disability and often includes epilepsy, infantile spasms, hand dystonia, lissencephaly, autism, or dysarthria. The review summarised known mutations and clinical manifestations but did not report any therapeutic interventions.
A review of mouse models of Bardet-Biedl Syndrome noted that intellectual disability affects 1% of the global population and is characterised by deficits in intellectual and adaptive functioning. The review stated that there are limited pharmacological interventions for intellectual disability, partly due to poor understanding of the condition and its heterogeneous nature, and that there are limited mouse models of intellectual disability. No drug treatment or clinical trial data were presented in any of the three abstracts.
What remains missing is any clinical trial testing a drug for intellectual disability-microcephaly-strabismus-behavioral abnormalities syndrome, any patient stratification by specific genetic mutation, and any funding for such a trial. The abstracts provide no evidence of efficacy for any compound.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Molecular Genetics & Genomic Medicine · 2017 · 39 citations · open access
Protein structure and phenotypic analysis of pathogenic and population missense variants in<i>STXBP1</i>
AbstractBackground Syntaxin-binding protein 1, encoded by STXBP1, is highly expressed in the brain and involved in fusing synaptic vesicles with the plasma membrane. Studies have shown that pathogenic loss-of-function variants in this gene result in various types of epilepsies, mostly beginning early in life. We were interested to model pathogenic missense variants on the protein structure to investigate the mechanism of pathogenicity and genotype–phenotype correlations. Methods We report 11 patients with pathogenic de novo mutations in STXBP1 identified in the first 4293 trios of the Deciphering Developmental Disorder (DDD) study, including six missense variants. We analyzed the structural locations of the pathogenic missense variants from this study and the literature, as well as population missense variants extracted from Exome Aggregation Consortium (ExAC). Results Pathogenic variants are significantly more likely to occur at highly conserved locations than population variants, and be buried inside the protein domain. Pathogenic mutations are also more likely to destabilize the domain structure compared with population variants, increasing the proportion of (partially) unfolded domains that are prone to aggregation or degradation. We were unable to detect any genotype–phenotype correlation, but unlike previously reported cases, most of the DDD patients with STXBP1 pathogenic variants did not present with very early-onset or severe epilepsy and encephalopathy, though all have developmental delay with intellectual disability and most display behavioral problems and suffered seizures in later childhood. Conclusion Variants across STXBP1 that cause loss of function can result in severe intellectual disability with or without seizures, consistent with a haploinsufficiency mechanism. Pathogenic missense mutations act through destabilization of the protein domain, making it prone to aggregation or degradation. The presence or absence of early seizures may reflect ascertainment bias in the literature as well as the broad recruitment strategy of the DDD study.
Oxford University Press eBooks · 2016 · 3 citations
Developmental Abnormalities Due to Mutations in the Aristaless-Related Homeobox Gene
AbstractAbstract Intellectual disability is a broad spectrum of neurodevelopmental disorders of the brain that combined affect approximately one in 50 individuals worldwide. X-linked intellectual disabilities represent a group of disorders where mutations arise on the X-chromosome. XLID is clinically complex and genetically heterogeneous. In excess of 100 genes are currently known. One of the most frequently mutated XLID genes (after e.g. FMR1 or MECP2) is the Aristaless related homeobox (ARX) gene. More than 110 mutations have been reported in ARX. The phenotype always involves intellectual disability and often also epilepsy, infantile spasms, hand dystonia, lissencephaly, autism or dysarthria. This chapter summarizes currently known mutations in ARX and their clinical manifestations and explores what is known about the underlying molecular and cellular mechanisms.
Iowa Research Online (The University of Iowa) · 2022 · 0 citations · open access
Behavioral and brain phenotypes of mouse models of Bardet-Biedl Syndrome
AbstractIntellectual disability (ID) is one of the most common neurodevelopmental disorders, affecting 1% of the population globally. Clinically, ID is characterized by a deficit in intellectual functioning and adaptive functioning. There are limited pharmacological interventions for ID, partially due to a poor understanding of ID and the heterogeneous nature of ID In addition, there are limited mouse models of ID.
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.
DeCure is a research and publication project, not medical advice and not a treatment. "DeCure for X" describes a research goal, not a claim that a cure exists. Backing a cure is a contribution to fund the research — it is not an investment, and confers no yield, royalty, equity or IP ownership. Papers are published open-access by the DeCure.ai DAO.
