DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for Fowler 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 moduleFowler 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 fowler 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
FLVCR choline and putative heme transporter 2 (FLVCR2) — FLVCR2 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 chtdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8QD0 · 2.8 Å · ligand CHOLINE ION (CHT). Experimental structure, not a prediction.
What the evidence adds up to
Fowler syndrome, also called proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome, is a rare autosomal recessive disorder caused by mutations in FLVCR2. The syndrome is characterised by glomerular vasculopathy in the central nervous system, severe hydrocephaly, hypokinesia and arthrogryposis. It has been considered prenatally lethal. Around 45 cases from 27 families had been reported by 2018, with bi-allelic mutations in FLVCR2 described in 15 families. A 2008 case report describes Fowler syndrome presenting as a Dandy-Walker malformation in a consanguineous family.
A 2015 report describes the first patients with Fowler syndrome and survival beyond infancy: a brother and sister with a homozygous pathogenic mutation in FLVCR2, c.1289C>T. Their phenotype included severe intellectual and neurologic disability with seizures, absence of functional movements, and no means of communication. Brain imaging showed calcifications, profound ventriculomegaly with only a thin edging of the cerebral cortex, and a hypoplastic cerebellum. This demonstrates that Fowler syndrome should be considered not only prenatally but also in severely affected children with gross ventriculomegaly on brain imaging.
A 2018 report describes an additional family with two affected fetuses carrying a novel homozygous mutation in FLVCR2. Structural analysis of known FLVCR2 mutations supports the hypothesis that a reduced heme import is the underlying disease mechanism, due to stabilisation of the occluded conformation or protein misfolding. The authors suggest heme deficiency as the major pathogenic mechanism of Fowler syndrome.
No drug treatment is mentioned in any of these abstracts. What is missing is any clinical trial, any tested intervention, any attempt to modulate heme import or compensate for FLVCR2 dysfunction in patients. The mechanism remains a hypothesis based on structural modelling. There is no patient stratification beyond genotype, no funding for a therapeutic development programme, and no trial design that could test a repurposed drug against this disease.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Clinical Genetics · 2015 · 25 citations
Mutations in <scp>FLVCR2</scp> associated with Fowler syndrome and survival beyond infancy
AbstractProliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH, OMIM 225790), also known as Fowler syndrome, is a rare autosomal recessive disorder, caused by mutations in FLVCR2. Hallmarks of the syndrome are glomerular vasculopathy in the central nervous system, severe hydrocephaly, hypokinesia and arthrogryphosis. The disorder is considered prenatally lethal. We report the first patients, a brother and a sister, with Fowler syndrome and survival beyond infancy. The patients present a phenotype of severe intellectual and neurologic disability with seizures, absence of functional movements, and no means of communication. Imaging of the brain showed calcifications, profound ventriculomegaly with only a thin edging of the cerebral cortex and hypoplastic cerebellum. Investigation with whole-exome sequencing (WES) revealed, in both patients, a homozygous pathogenic mutation in FLVCR2, c.1289C>T, compatible with a diagnosis of Fowler syndrome. The results highlight the power of combining WES with a thorough clinical examination in order to identify disease-causing mutations in patients whose clinical presentation differs from previously described cases. Specifically, the findings demonstrate that Fowler syndrome is a diagnosis to consider, not only prenatally but also in severely affected children with gross ventriculomegaly on brain imaging.
Molecular Genetics & Genomic Medicine · 2018 · 19 citations · open access
Proliferative vasculopathy and hydranencephaly–hydrocephaly syndrome or Fowler syndrome: Report of a family and insight into the disease's mechanism
AbstractBACKGROUND: Fowler syndrome is a rare autosomal recessive disorder characterized by hydranencephaly-hydrocephaly and multiple pterygium due to fetal akinesia. To date, around 45 cases from 27 families have been reported, and the pathogenic bi-allelic mutations in FLVCR2 gene described in 15 families. The pathogenesis of this condition has not been fully elucidated so far. METHODS: We report on an additional family with two affected fetuses carrying a novel homozygous mutation in FLVCR2 gene, and describe the impact of known mutants on the protein structural and functional impairment. RESULTS: The present report confirms the genetic homogeneity of Fowler syndrome and describes a new FLVCR2 mutation affecting the protein function. The structural analysis of the present and previously published FLVCR2 mutations supports the hypothesis of a reduced heme import as the underlying disease's mechanism due to the stabilization of the occluded conformation or a protein misfolding. CONCLUSION: Our data suggest the hypothesis of heme deficiency as the major pathogenic mechanism of Fowler syndrome.
Pediatric and Developmental Pathology · 2008 · 9 citations
Fowler Syndrome Presenting as a Dandy-Walker Malformation: A Second Case Report
AbstractFowler syndrome, also known as proliferative vasculopathy and hydrocephaly-hydranencephaly, is a lethal condition characterized by hydrocephalus associated with progressive destruction of central nervous system tissue as a result of an unusual and characteristic proliferative vasculopathy. The occurrence of Fowler syndrome in consanguineous families and recurrence in both sexes are suggestive of an autosomal recessive transmission. We present the second case of Fowler syndrome presenting as a Dandy-Walker malformation, in a consanguineous family.
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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