DeCure for Blepharophimosis-impaired intellectual development syndrome
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for blepharophimosis-impaired intellectual development syndrome — 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 moduleBlepharophimosis-impaired intellectual development syndrome 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 blepharophimosis-impaired intellectual development 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 2012, biallelic UBE3B mutations were identified in four patients from three families with an autosomal-recessive blepharophimosis-ptosis-intellectual-disability syndrome. The patients had developmental delay, growth retardation with small head circumference, facial dysmorphisms, and low cholesterol levels. Disruption of mouse Ube3b reduced viability and recapitulated reduced weight and brain size and downregulation of cholesterol synthesis. By 2020, only 24 patients with UBE3B-related BPID had been described worldwide. A report of nine additional Egyptian patients from six families found five novel homozygous UBE3B variants; brain MRI in seven patients showed hypogenesis or near-complete agenesis of corpus callosum. New findings included spherophakia, subvalvular aortic stenosis, and hypoplastic nails and terminal phalanges.
A 1998 series of 22 children referred for blepharophimosis found that 8 of 12 assessable children with blepharophimosis syndrome had mental retardation or developmental delay. All eight children with a malformation syndrome other than blepharophimosis syndrome were mentally retarded or developmentally delayed. The authors recommended careful evaluation for underlying conditions and observation for developmental disabilities because of the frequent association.
In 2024, a distinct DNA methylation episignature was shared by 15 individuals with BIS-causing SMARCA2 pathogenic variants and 12 individuals with class II Helsmoortel-Van Der Aa Syndrome caused by truncating ADNP variants. This was described as the first evidence of a phenotype-specific episignature biomarker shared across distinct genetic conditions that also have unique gene-specific episignatures. A 2011 review noted that intellectual disability was considered immutable and that current medical practices aimed at symptom relief, not altering cognitive deficits, though it raised the possibility that pharmaceutical therapies might become available for Fragile X syndrome. A 2024 abstract described an anti-sense oligonucleotide therapeutic under development for RhoBTB2-related epileptic encephalopathy, a different disorder with severe to profound intellectual disability and early-onset seizures.
What is still missing: no clinical trial data exist for any drug targeting UBE3B deficiency or SMARCA2-related BIS. No animal model has been used to test a small molecule or gene therapy for these conditions. The natural history of BPID remains poorly characterised beyond case series, and no patient stratification by genotype or episignature has been linked to outcomes. Funding for drug development in these ultra-rare syndromes is absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
The American Journal of Human Genetics · 2012 · 96 citations · open access
Deficiency for the Ubiquitin Ligase UBE3B in a Blepharophimosis-Ptosis-Intellectual-Disability Syndrome
AbstractUbiquitination plays a crucial role in neurodevelopment as exemplified by Angelman syndrome, which is caused by genetic alterations of the ubiquitin ligase-encoding UBE3A gene. Although the function of UBE3A has been widely studied, little is known about its paralog UBE3B. By using exome and capillary sequencing, we here identify biallelic UBE3B mutations in four patients from three unrelated families presenting an autosomal-recessive blepharophimosis-ptosis-intellectual-disability syndrome characterized by developmental delay, growth retardation with a small head circumference, facial dysmorphisms, and low cholesterol levels. UBE3B encodes an uncharacterized E3 ubiquitin ligase. The identified UBE3B variants include one frameshift and two splice-site mutations as well as a missense substitution affecting the highly conserved HECT domain. Disruption of mouse Ube3b leads to reduced viability and recapitulates key aspects of the human disorder, such as reduced weight and brain size and a downregulation of cholesterol synthesis. We establish that the probable Caenorhabditis elegans ortholog of UBE3B, oxi-1, functions in the ubiquitin/proteasome system in vivo and is especially required under oxidative stress conditions. Our data reveal the pleiotropic effects of UBE3B deficiency and reinforce the physiological importance of ubiquitination in neuronal development and function in mammals.
American Journal of Medical Genetics · 1998 · 26 citations
Blepharophimosis: A causally heterogeneous malformation frequently associated with developmental disabilities
AbstractWe report on 22 individuals referred for genetic evaluation because of blepharophimosis. Fourteen of these patients had the blepharophimosis syndrome: 5 familial and 9 sporadic. Mental retardation or developmental delay was seen in 8 of the 12 children in whom this could be assessed. Eight of 22 children had a malformation syndrome other than the blepharophimosis syndrome. All 8 of these children were mentally retarded or developmentally delayed. Two of these 8 had recognized disorders (branchio-oto-renal syndrome and a ring 4 chromosome); the remaining 6 had unrecognized malformation syndromes. Based on this information, it is suggested that children with blepharophimosis be evaluated carefully for underlying conditions and that they be observed for developmental disabilities because of the frequent association.
Reproductive Biology and Endocrinology · 2016 · 25 citations · open access
Effect of bone morphogenetic protein-4 on in vitro growth, steroidogenesis and subsequent developmental competence of the oocyte-granulosa cell complex derived from bovine early antral follicles
AbstractBACKGROUND: Bone morphogenetic proteins (BMPs) play important regulatory roles during folliculogenesis. Theca-derived BMP-4 may be beneficial to in vitro growth culture of early antral follicle-derived oocyte-granulosa cell complexes (OGCs), which is lacking in theca-derived products. METHODS: BMP-4 (0 [control], 10 and 50 ng/mL) was added to growth culture medium. Growth, steroidogenesis and the subsequent developmental competence of OGCs derived from bovine early antral follicles (0.5-1 mm) were examined. RESULTS: At 4, 8 and 12 days of growth culture, progesterone production by granulosa cells was suppressed by the addition of BMP-4 compared to the control (P < 0.05). At 12 days, both the OGC survivability and granulosa cell number in the 50 ng/mL BMP-4 treated group were lower than those of control (48.2 % vs. 67.8 %; 4.96 × 10(4) vs. 8.5 × 10(4) cells; P < 0.05, respectively), while no difference was found between 10 ng/mL and the control. The mean diameters of granulosa cell in the BMP-4 treated groups were smaller than that of the control (P < 0.05). However, the granulosa cell viability, oocyte diameter, oocyte nuclear maturation rate and normal fertilization rate were similar in all of the experimental groups, regardless of the amount of BMP-4 addition (P ˃ 0.05). BMP-4 treated in vitro-grown oocytes showed lower blastocyst rates than untreated ones (P < 0.05). CONCLUSIONS: BMP-4 addition during in vitro growth culture suppressed progesterone production and decreased the diameter of granulosa cells, suggesting its effect on steroidogenesis; importantly, it did not affect oocyte growth, nuclear maturation and fertilization. However, BMP-4 impaired subsequent embryonic development, and in higher concentration (50 ng/mL) even compromised OGC viability by suppressing proliferation of granulosa cells.
ACS Chemical Neuroscience · 2011 · 19 citations · open access
Fragile X Syndrome: An Update on Developing Treatment Modalities
AbstractIntellectual disability (ID; mental retardation) is considered an immutable condition. Current medical practices are aimed at relieving symptoms and not at altering the underlying cognitive deficits. Scientific advancements from the past decade have led to the exciting possibility that ID may now be treatable. Moreover, pharmaceutical therapies targeting the most common form of inherited ID, Fragile X syndrome (FXS), may become the new benchmark for central nervous system (CNS) drug discovery: seeking cures for neurodevelopmental disorders.
American Journal of Medical Genetics Part A · 2020 · 8 citations
Blepharophimosis‐ptosis‐intellectual disability syndrome: A report of nine Egyptian patients with further expansion of phenotypic and mutational spectrum
AbstractBlepharophimosis-ptosis-intellectual disability syndrome (BPID) is an extremely rare recognizable blepharophimosis intellectual disability syndrome (BID). It is caused by biallelic variants in the UBE3B gene with only 24 patients described worldwide. Herein, we report on the clinical, brain imaging and molecular findings of additional nine patients from six unrelated Egyptian families. Patients presented with the characteristic features of the syndrome including blepharophimosis, ptosis, upslanted palpebral fissures with epicanthic folds, hypertelorism, long philtrum, high arched palate, micrognathia, microcephaly, and intellectual disability. Other findings were congenital heart disease (5 patients), talipes equinovarus (5 patients), genital anomalies (5 patients), autistic features (4 patients), cleft palate (2 patients), hearing loss (2 patients), and renal anomalies (1 patient). New or rarely reported findings were spherophakia, subvalvular aortic stenosis and hypoplastic nails, and terminal phalanges. Brain MRI, performed for 7 patients, showed hypogenesis or almost complete agenesis of corpus callosum. Genetic studies revealed five novel homozygous UBE3B variants. Of them, the c.1076G>A (p.W359*) was found in three patients from two unrelated families who shared similar haplotype suggesting a likely founder effect. Our results strengthen the clinical, dysmorphic, and brain imaging characteristic of this unique type of BID and extend the mutational spectrum associated with the disorder.
American Journal of Medical Genetics Part C Seminars in Medical Genetics · 2024 · 7 citations · open access
Blepharophimosis with intellectual disability and Helsmoortel‐Van Der Aa Syndrome share episignature and phenotype
AbstractBlepharophimosis with intellectual disability (BIS) is a recently recognized disorder distinct from Nicolaides-Baraister syndrome that presents with distinct facial features of blepharophimosis, developmental delay, and intellectual disability. BIS is caused by pathogenic variants in SMARCA2, that encodes the catalytic subunit of the superfamily II helicase group of the BRG1 and BRM-associated factors (BAF) forming the BAF complex, a chromatin remodeling complex involved in transcriptional regulation. Individuals bearing variants within the bipartite nuclear localization (BNL) signal domain of ADNP present with the neurodevelopmental disorder known as Helsmoortel-Van Der Aa Syndrome (HVDAS). Distinct DNA methylation profiles referred to as episignatures have been reported in HVDAS and BAF complex disorders. Due to molecular interactions between ADNP and BAF complex, and an overlapping craniofacial phenotype with narrowing of the palpebral fissures in a subset of patients with HVDAS and BIS, we hypothesized the possibility of a common phenotype-specific episignature. A distinct episignature was shared by 15 individuals with BIS-causing SMARCA2 pathogenic variants and 12 individuals with class II HVDAS caused by truncating pathogenic ADNP variants. This represents first evidence of a sensitive phenotype-specific episignature biomarker shared across distinct genetic conditions that also exhibit unique gene-specific episignatures.
Genetics in Medicine Open · 2024 · 1 citations · open access
O42: Development of an anti-sense oligonucleotide therapeutic targeting RhoBTB2-related epileptic encephalopathy
AbstractRHOBTB2 encodes a member of the atypical Rho GTPase containing a GTPase domain and two tandem BTB domains. The BTB domains are involved in interacting with the Cullin3-dependent ubiquitin ligase complex, mediating ubiquitination, and recruiting substrates to the complex. Pathogenic de novo missense variants clustering in the BTB domains were reported to cause autosomal dominant developmental and epileptic encephalopathy 64 [DEE64; OMIM 618004]. DEE64 is a neurodevelopmental disorder characterized by onset of seizures within the first year of life, severe to profound intellectual disability, movement disorders, postnatal microcephaly, and nonspecific dysmorphic features.
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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