DeCure for Hyperphosphatasia-intellectual disability syndrome
DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for hyperphosphatasia-intellectual disability syndrome — screening already-approved drugs against its 13-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleHyperphosphatasia-intellectual disability syndrome maps to a 13-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 hyperphosphatasia-intellectual disability 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.
Molecular view
erb-b2 receptor tyrosine kinase 2 (ERBB2) — ERBB2 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 7MN5 · 2.93 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
A 2022 case report describes a five-year-old girl with hyperphosphatasia-intellectual disability syndrome type 3 (HPMRS3), caused by compound heterozygous variants in the PGAP2 gene. She had global developmental delay, precocious puberty, and persistently raised plasma alkaline phosphatase. Cerebrospinal fluid analysis revealed low pyridoxal phosphate and low 5-methyltetrahydrofolate, with raised homovanillic acid. Supplementation with pyridoxine and folinic acid normalised those biochemical abnormalities. The authors state the patient continued to make developmental progress with significant improvement in speech and fine motor skills, but this is a single case, not a controlled trial, and no quantitative measures of improvement (e.g., standardised test scores) are reported.
The same abstract notes that hyperphosphatasia with mental retardation syndrome (Mabry syndrome) is characterised by moderate to severe intellectual disability, dysmorphic features, hypotonia, seizures, and persistent hyperphosphatasia. Six GPI anchor defects present with this clinical phenotype. The authors comment that there is currently no treatment that can lead to improved clinical outcomes for this group of disorders, and they propose that the CSF abnormalities may have management implications.
Two older papers provide context on intellectual disability in syndromic conditions generally. A 2006 study of 31 children with craniosynostosis (13 syndromic, 18 nonsyndromic) found mean IQ was 83.1 in the syndromic group and 104.7 in the nonsyndromic group. 77 percent of syndromic children had normal intelligence. That study is not about hyperphosphatasia-intellectual disability syndrome, but it shows that syndromic craniosynostosis is not synonymous with intellectual disability. A 2000 annotation reviews the heightened prevalence of psychopathology in children with intellectual disability and notes that genetic syndromes have specific psychiatric vulnerabilities.
What is still missing: no controlled trial of pyridoxine and folinic acid for HPMRS3 exists; the evidence is limited to a single case with no blinding, no comparator, and no objective developmental endpoints. Larger, genetically stratified cohorts are needed, and funding for such studies is absent. The biochemical rationale is plausible but unvalidated in a systematic way.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Plastic & Reconstructive Surgery · 2006 · 86 citations
Intellectual Outcomes in Children and Adolescents with Syndromic and Nonsyndromic Craniosynostosis
AbstractBACKGROUND: Craniosynostosis, the premature fusion of the skull bones, is a congenital deformity that has functional and morphologic implications. Cranial vault reconstructive surgery is required to improve skull shape and increase intracranial volume. Craniosynostosis disorders carry a risk of brain insult and associated neurologic and cognitive dysfunction. This study investigated the long-term effects of craniosynostosis on intelligence in children and adolescents with syndromic and nonsyndromic disorders who had undergone cranial expansion surgery during infancy. METHODS: Global intellectual evaluations were obtained on 31 children aged 7 to 16 years with mixed syndromic (n = 13) and nonsyndromic (n = 18) craniosynostoses. Results of intellectual assessment were compared with norm-referenced data. Age at surgery and gender comparisons were also made. RESULTS: Mean +/- SD general intelligence quotient of the total sample was within the average range (intelligence quotient, 95.6 +/- 21.2). Intellectual functioning was significantly lower in children with syndromic craniosynostosis (mean intelligence quotient, 83.1 +/- 21.9) than nonsyndromic craniosynostosis (mean intelligence quotient, 104.7 +/- 15.8). The majority of children with syndromic craniosynostosis (77 percent) were of normal intelligence. Children with nonsyndromic craniosynostosis did not display obvious evidence of intellectual dysfunction. There were no age or gender differences in intellectual outcomes in this sample. CONCLUSIONS: Findings are contrary to the historical impression that has regarded syndromic craniosynostosis as synonymous with intellectual disability. Children with nonsyndromic craniosynostosis are of normal intelligence during their school-age years.
Journal of Child Psychology and Psychiatry · 2000 · 31 citations
Annotation: Psychopathology in Children with Intellectual Disability
AbstractRecent advances are reviewed in understanding the heightened prevalence of psychopathology and maladaptive behavior among children with intellectual disability. Researchers have traditionally emphasized measurement and prevalence issues, using either psychiatric assessments or rating scales to identify the prevalence of various problems in children with intellectual disability. Yet the time is ripe to shift directions, and identify more precisely why children are at increased risk for psychopathology to begin with. Although several “biopsycho-social” hypotheses are reviewed, a particularly promising line of work links psychopathology to genetic intellectual disability syndromes. Psychiatric vulnerabilities in several syndromes are reviewed, as are the advantages of phenotypic work for understanding psychopathology among children with intellectual disability more generally.
Hyperphosphatasia with mental retardation syndrome 3: Cerebrospinal fluid abnormalities and correction with pyridoxine and Folinic acid
AbstractAbstract Glycosylphosphatidylinositol anchored proteins (GPI‐APs) represent a class of molecules attached to the external leaflet of the plasma membrane by the GPI anchor where they play important roles in numerous cellular processes including neurogenesis, cell adhesion, immune response and signalling. Within the group of GPI anchor defects, six present with the clinical phenotype of Hyperphosphatasia with Mental Retardation Syndrome (HPMRS, Mabry Syndrome) characterized by moderate to severe intellectual disability, dysmorphic features, hypotonia, seizures and persistent hyperphosphatasia. We report the case of a 5‐year‐old female with global developmental delay associated with precocious puberty and persistently raised plasma alkaline phosphatase. Targeted next generation sequencing analysis of the HPMRS genes identified novel compound heterozygous variants in the PGAP2 gene (c.103del p.(Leu35Serfs*90)and c.134A > Gp.(His45Arg)) consistent with the diagnosis of HPMRS type 3. Cerebrospinal fluid (CSF) neurotransmitter analysis showed low levels of pyridoxal phosphate and 5‐methyltetrahydrofolate and raised homovanillic acid. Supplementation with pyridoxine and folinic acid led to normalization of biochemical abnormalities. The patient continues to make developmental progress with significant improvement in speech and fine motor skills. Our reported case expands the clinical spectrum of HPMRS3 in which multisystem involvement is being increasingly recognized. Furthermore, it shows that miss‐targeting GPI‐APs and the effect on normal cellular function could provide a physiopathologic explanation for the CSF biochemical abnormalities with management implications for a group of disorders that currently has no treatment that can lead possibly to improved clinical outcomes.
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.
