DeCure for Neurodegenerative syndrome due to cerebral folate transport deficiency
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for neurodegenerative syndrome due to cerebral folate transport 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 moduleNeurodegenerative syndrome due to cerebral folate transport 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
No approved-drug candidate for neurodegenerative syndrome due to cerebral folate transport deficiency 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
folate receptor alpha (FOLR1) — FOLR1 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 foldrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 4LRH · 2.8 Å · ligand FOLIC ACID (FOL). Experimental structure, not a prediction.
What the evidence adds up to
Cerebral folate deficiency is defined by low cerebrospinal fluid folate with normal serum folate. A 2015 review notes that treatment with folate supplementation generally improves neurological outcome in some patients, but stresses that the choice of folate form is essential because folinic acid and 5-methyltetrahydrofolate are efficiently transported to the brain while other forms are not. The review states there is no general consensus on oral doses and calls for further clinical trials.
A 2012 case report describes a 58-year-old woman with progressive memory loss and myoclonus whose cerebrospinal fluid showed low 5-methyltetrahydrofolate and whose serum contained folate receptor 1 blocking antibodies. After six months of folinic acid supplementation her clinical symptoms resolved. The authors call this the first reported case of adult-onset cerebral folate deficiency and suggest it could represent a treatable form of early-onset dementia.
Two 2024 paediatric cases of cerebral folate transport deficiency due to FOLR1 gene mutations are reported. An eight-year-old and a nine-month-old female presented with delayed milestones, regression, seizures, intention tremors, microcephaly, hypotonia, hyperreflexia, and unsteady gait. Neuroimaging showed dilated ventricles, cerebellar atrophy, and brain calcifications. Whole exome sequencing revealed a homozygous nonsense pathogenic variant in FOLR1. A twelve-year-old female with global developmental delay, myoclonic jerks, cognitive regression, hypotonia, hyperreflexia, intention tremors, and unbalanced gait had bilateral basal ganglia and periventricular calcifications with brain atrophy. Genetic testing showed a homozygous pathogenic variant in FOLR1. Both patients were started on intramuscular folinic acid injections, which decreased seizure frequency, but seizures did not stop completely because therapy was initiated late. The authors conclude that response to folinic acid is partial if diagnosis and treatment are delayed.
A 2013 study of cerebral folate transport deficiency, an autosomal recessive disorder causing very low cerebrospinal fluid 5-methyltetrahydrofolate and encephalopathy after the second year of life, investigated the phenotypic spectrum and aimed to enable individual optimisation of treatment with calcium folinate in different modes of application. What remains missing are standardised dosing guidelines, prospective trials that stratify patients by age at treatment initiation and genetic subtype, and funding for early diagnostic screening so that treatment can begin before irreversible neurological damage has occurred.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Journal of Neurology Neurosurgery & Psychiatry · 1986 · 54 citations · open access
Subacute combined degeneration of the cord due to folate deficiency: response to methyl folate treatment.
AbstractSubacute combined degeneration of the cord is a rare complication of folate deficiency. Disturbance of methylation reactions in nervous tissue probably underlie subacute combined degeneration of the cord arising from folate as well as vitamin B12 deficiency. Methyl tetrahydrofolate is the form in which folic acid is transported into the CNS. Therefore methyl tetrahydrofolate treatment of the neurological and psychiatric manifestations of folate deficiency would seem to be theoretically advantageous. A case of subacute combined degeneration of the cord due to dietary folate deficiency and associated with an organic brain syndrome is reported. There was striking haematological, neurological and psychiatric response to methyl folate treatment.
Expert Review of Neurotherapeutics · 2015 · 28 citations
Clinical, etiological and therapeutic aspects of cerebral folate deficiency
AbstractCerebral folate deficiency is defined as any neurological condition associated with low cerebrospinal fluid folate concentrations. It is becoming increasingly associated with several neurological diseases, either genetic or environmental. Treatment of cerebral folate deficiency by folate supplementation is generally effective, improving the neurological outcome of some patients. However, to treat cerebral folate deficiency, the proper choice of one of the available folate forms is essential. The distinct brain folate metabolism features compared with peripheral folate metabolic pathways strongly suggest the investigation of different folate forms, such as the biologically active folinic acid and 5-methyltetrahydrofolate, since they are efficiently transported to the brain. Regarding the oral doses of the different folate forms, despite the fact that there are some recommendations, there is no general consensus. Further investigation and designing clinical trials are advisable to elucidate these aspects.
AbstractOBJECTIVE: To report new manifestations of cerebral folate deficiency, a rare metabolic autoimmune syndrome,in an adult. DESIGN: Case report. SETTING: University teaching hospital. PATIENT: A 58-year-old woman with progressive memory loss and myoclonus presented for medical attention. Results of cerebral spinal fluid analysis showed low levels of tetrahydrobiopterin and 5-methyltetrahydrofolate. The patient's serum folate level was normal. Serum contained folate receptor 1 blocking and binding antibodies. RESULTS: The patient was treated successfully with folinic acid supplementation, and after 6 months of treatment,clinical symptoms had resolved. CONCLUSIONS: To our knowledge, we report the first case of adult-onset cerebral folate deficiency. Furthermore, this condition could represent a treatable form of early-onset dementia.
Journal of Epilepsy Research · 2024 · 2 citations · open access
Cerebral Folate Transport Deficiency in 2 Cases with Intractable Myoclonic Epilepsy
AbstractCerebral folate transport deficiency due to folate receptor 1 gene (FOLR1) gene mutation results from impaired folate transport across the blood: choroidplexus: cerebrospinal fluid (CSF) barrier. This leads to low CSF 5-methyltetrahydrofolate, the active folate metabolite. We are reporting two children with this treatable cerebral folate transport deficiency. Eight years and 9-month-old female presented with delayed milestones followed by regression, seizures, and intention tremors. On examination child had microcephaly, generalized hypotonia, hyperreflexia, unsteady gait, and incoordination. Magnetic resonance imaging (MRI) of brain revealed dilated ventricular system and cerebellar atrophy. Computed tomography (CT) of brain showed brain calcifications. Whole exome sequencing was finally performed, revealing homozygous nonsense pathogenic variant in FOLR1 gene in exon 3 c.C382T p.R128W, confirming the diagnosis of cerebral folate deficiency. Twelve-year-old female child presented with global developmental delay since birth, myoclonic jerks and cognitive regression. Child had generalized hypotonia and hyperreflexia. Her coordination was markedly affected with intention tremors andunbalanced gait. CT brain showed bilateral basal ganglia and periventricular calcifications with brain atrophic changes. MRI brain showed a prominent cerebellar folia with mild brain atrophic changes. Genetic testing showed a homozygous pathogenic variant was identified in FOLR1 C.327_328 delinsAC, p.Cys109Ter. Both patients were started on intramuscular folinic acid injections with a decrease in seizure frequency. However, their seizures did not stop completely due to late initiation of therapy. In conclusion, cerebral folate transport deficiency should be suspected in every child with global developmental delay, intractable myoclonic epilepsy, ataxia with neuroimaging suggesting cerebellar atrophy and brain calcifications. Response to folinic acid supplementation is partial if diagnosed late and treatment initiation is delayed.
Stepwise adaptation of treatment with calcium folinate in different modes of application leads to optimal therapeutic results for patients with cerebral folate transport deficiency
AbstractAims: Cerebral folate transport deficiency (CFTD) is an autosomal recessively inherited disease that is caused by a brain-specific folate transport defect. All currently known patients show very low concentrations of 5-methyltetrahydrofolate in the cerebrospinal fluid and develop an encephalopathy after the second year of life. We investigated patients suffering from CFTD to understand the phenotypic spectrum and to enable individual optimization of treatment.
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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