DeCure for Epilepsy, familial focal, with variable foci 1
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for epilepsy, familial focal, with variable foci 1 — screening already-approved drugs against its 4-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleEpilepsy, familial focal, with variable foci 1 maps to a 4-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 epilepsy, familial focal, with variable foci 1 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
NPR3 like, GATOR1 complex subunit (NPRL3) — NPRL3 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 gdpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 8FW5 · 3.08 Å · ligand GUANOSINE-5'-DIPHOSPHATE (GDP). Experimental structure, not a prediction.
What the evidence adds up to
Familial focal epilepsy with variable foci (FFEVF) is a rare autosomal dominant syndrome in which different family members have focal seizures arising from different cortical regions. A 2005 review noted that at that time the only genes identified for any familial focal epilepsy were for autosomal-dominant nocturnal frontal lobe epilepsy and familial lateral temporal lobe epilepsy, and that functional studies were the next step toward new therapeutic strategies. A 2012 study of two Australian families confirmed chromosome 22q12 as the solitary locus for FFEVF, extending the clinical spectrum. A 2019 report described a two-generation Argentine family with a DEPDC5 gene mutation (c.4718T>C; p.L1573P) in which the three affected members had a mean onset age of nine years, normal neurological examination and neuroimaging, and all three were seizure-free at the time of reporting despite initially frequent seizures.
More recent work has focused on NPRL3 mutations. A 2021 study of a six-generation Chinese family with a novel NPRL3 mutation (c.316C>T; p.Q106*) found that both mRNA level and protein expression of NPRL3 were decreased in peripheral blood cells of mutation carriers compared with healthy family members, and that expression of downstream molecule Phospho-p70 S6 kinase was increased. That study called for further in vitro and animal experiments to evaluate the role of NPRL3 loss-of-function in epileptogenesis. A 2023 study of a Chinese family with an NPRL3 c.1137dupT variant (four patients, one healthy member) reported a wide range of onset age (4 months to 31 years), diverse seizure types, variable foci (frontal or temporal lobe), different seizure times and frequencies, and different therapeutic effects ranging from refractory epilepsy to almost seizure-free. MRI was normal in all patients; EEG showed epileptiform discharge and slow wave. Real-time qPCR showed significantly different relative quantities of mRNA between patients and healthy individuals, and RT-PCR revealed abnormal splicing in patients. Despite having the same gene variant, different family members had different mRNA splicing, which the authors suggested might cause different phenotypes.
No drug treatment is tested or recommended in any of these abstracts. The evidence consists entirely of small family studies describing genetic findings and clinical variability. What is missing is any large-scale natural history study, any prospective trial of a targeted therapy (for example, an mTOR pathway inhibitor, given the GATOR1 involvement), and any systematic attempt to stratify patients by specific gene variant or splicing pattern. The field remains at the stage of genetic discovery and phenotypic description, with no interventional data.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Epilepsia · 2005 · 41 citations
Genetic Focal Epilepsies: State of the Art and Paths to the Future
AbstractThe concept of genetic focal epilepsies is relatively new as compared to awareness of the importance of genetic factors in the generalized epilepsies. However, in the past decade, there has been increasing recognition of families with dominantly inherited partial epilepsies. Better definition of the phenotypes allows identification of distinct syndromes. The main familial focal epilepsies are autosomal-dominant nocturnal frontal lobe epilepsy (ADNFLE), familial mesial TLE (FMTLE), familial lateral TLE (FLTLE), and familial partial epilepsy with variable foci (FPEVF). The only genes identified so far are those for ADNFLE and FLTLE. In these disorders, functional studies are the next step and could provide advances leading to clarification of the pathophysiology as well as to new therapeutic strategies. At present, we can provide genetic counseling and a more accurate prognosis for most of the familial focal epilepsies. Greater awareness of the genetic basis in this group of disorders by the treating physicians is essential for identification of new families. This will allow further linkage studies, candidate gene screening, and identification of new genes, which will hopefully result in genetically based prevention and treatment.
Familial focal epilepsy with variable foci mapped to chromosome 22q12: Expansion of the phenotypic spectrum
AbstractWe aimed to refine the phenotypic spectrum and map the causative gene in two families with familial focal epilepsy with variable foci (FFEVF). A new five-generation Australian FFEVF family (A) underwent electroclinical phenotyping, and the original four-generation Australian FFEVF family (B) (Ann Neurol, 44, 1998, 890) was re-analyzed, including new affected individuals. Mapping studies examined segregation at the chromosome 22q12 FFEVF region. In family B, the original whole genome microsatellite data was reviewed. Five subjects in family A and 10 in family B had FFEVF with predominantly awake attacks and active EEG studies with a different phenotypic picture from other families. In family B, reanalysis excluded the tentative 2q locus reported. Both families mapped to chromosome 22q12. Our results confirm chromosome 22q12 as the solitary locus for FFEVF. Both families show a subtly different phenotype to other published families extending the clinical spectrum of FFEVF.
American Journal of Neuroradiology · 2022 · 19 citations · open access
Simultaneously Acquired MRI Arterial Spin-Labeling and Interictal FDG-PET Improves Diagnosis of Pediatric Temporal Lobe Epilepsy
Abstract<h3>BACKGROUND AND PURPOSE:</h3> Interictal FDG-PET scans are a routine diagnostic technique for the identification of epileptogenic foci in the presurgical work-up of medically refractory pediatric epilepsy. With the advent of PET/MR imaging, it has become possible to simultaneously acquire FDG-PET and arterial spin-labeling perfusion data. The objective of this study was to evaluate whether the incorporation of arterial spin-labeling data with interictal FDG-PET could improve the diagnostic performance metrics of FDG-PET for identification of epileptogenic foci. <h3>MATERIALS AND METHODS:</h3> Forty-five pediatric patients with a mean age of 10.8 years were retrospectively included in this study. These patients all underwent PET/MR imaging to diagnose suspected focal epilepsy. <h3>RESULTS:</h3> When compared to interpretations of interictal FDG findings alone, FDG combined with arterial spin-labeling findings resulted in significantly decreased sensitivity (0.64 versus 0.52, <i>P </i>= .02), significantly increased specificity (0.50 versus 0.75, <i>P </i>= .04), and an increased positive predictive value (0.59 versus 0.75). The decreased sensitivity was found to be primarily driven by patients with extratemporal lobe epilepsy, as a subgroup analysis showed decreased sensitivity for patients with extratemporal epilepsy (0.52 versus 0.38, <i>P </i>= .04), but not for temporal epilepsy (0.83 versus 0.75, <i>P </i>= .16). Additionally, substantial agreement between focal FDG hypometabolism and arterial spin-labeling hypoperfusion was demonstrated with the Cohen κ (0.70, <i>P </i>< .01). <h3>CONCLUSIONS:</h3> These findings suggest that simultaneously acquired interictal FDG-PET and arterial spin-labeling data can improve the diagnosis of epileptogenic foci, especially in the setting of temporal lobe epilepsy where they improve specificity and positive predictive value, with preservation of sensitivity.
<i>DEPDC5</i> mutation and familial focal epilepsy with variable foci: genotype and phenotype of a family
AbstractFamilial focal epilepsy with variable foci is a relatively rare autosomal disease with an unclear incidence, which is characterized by focal seizures arising from different cortical regions in different family members. We describe three members of a two-generation Argentine family with familial focal epilepsy with variable foci syndrome and a DEPDC5 gene mutation. The mean onset age was nine years old. The father experienced episodes with occipital semiology and both siblings exhibited frontal lobe seizures. Their neurological examination and neuroimaging studies were normal. All three patients are currently seizure-free, in spite of initially experiencing frequent seizures. Complete exome sequencing revealed a new DEPDC5 gene mutation (NM_001242896: c.4718T>C; p.L1573P). This study of a family with clinical characteristics that met all the criteria for familial focal epilepsy with variable foci demonstrates the usefulness of exome sequencing as a diagnostic tool. [Published with video sequence on www.epilepticdisorders.com].
Abstract<div><p>Objective</p><p>Familial focal epilepsy with variable foci (FFEVF) is a rare type of focal epilepsy syndrome; it is associated with <i>NPRL3</i> variant. However, relevant reports are rare in China. We aimed to analyze the clinical features of Chinese patients with FFEVF to understand further the differences between various <i>NPRL3</i> variants and explored the effect of <i>NPRL3</i> variant on mRNA.</p><p>Methods</p><p>We ran a full workup on a family with FFEVF (four patients, one healthy member): an inquiry of medical history, cranial magnetic resonance imaging (MRI), electroencephalogram (EEG), and whole exon sequencing. Their clinical features were compared with those of other FFEVF patients in published reports. The mRNA splicing changes were analyzed quantitatively and qualitatively using real-time quantitative—polymerase chain reaction (q-PCR) and reverse transcription (RT)-PCR and compared between our patients and healthy individuals.</p><p>Results</p><p>Patients with <i>NPRL3</i>: c.1137dupT variant had a wide range of onset age (4 months to 31 years), diverse seizure types, variable foci (frontal lobe/temporal lobe), different seizure times (day/night) and frequencies (monthly/seldom/every day), different therapeutic effects (refractory epilepsy/almost seizure free), normal MRI, and abnormal EEG (epileptiform discharge, slow wave). The phenotypic spectrum with different <i>NPRL3</i> variants was either similar or different. Significantly different relative quantities of mRNA were found between patients and healthy individuals in real-time qPCR. Abnormal splicing was observed in patients compared with healthy individual in RT-PCR. Despite having the same gene variant, different family members had different mRNA splicing, possibly causing different phenotypes.</p><p>Conclusion</p><p>The clinical features of FFEVF varied, and auxiliary inspection was atypical. <i>NPRL3</i>: c.1137dupT could change the relative quantity of mRNA and cause abnormal splicing, which might produce different phenotypes in different family members.</p></div>
Abstract<div><p>Objective</p><p>Familial focal epilepsy with variable foci (FFEVF) is a rare type of focal epilepsy syndrome; it is associated with <i>NPRL3</i> variant. However, relevant reports are rare in China. We aimed to analyze the clinical features of Chinese patients with FFEVF to understand further the differences between various <i>NPRL3</i> variants and explored the effect of <i>NPRL3</i> variant on mRNA.</p><p>Methods</p><p>We ran a full workup on a family with FFEVF (four patients, one healthy member): an inquiry of medical history, cranial magnetic resonance imaging (MRI), electroencephalogram (EEG), and whole exon sequencing. Their clinical features were compared with those of other FFEVF patients in published reports. The mRNA splicing changes were analyzed quantitatively and qualitatively using real-time quantitative—polymerase chain reaction (q-PCR) and reverse transcription (RT)-PCR and compared between our patients and healthy individuals.</p><p>Results</p><p>Patients with <i>NPRL3</i>: c.1137dupT variant had a wide range of onset age (4 months to 31 years), diverse seizure types, variable foci (frontal lobe/temporal lobe), different seizure times (day/night) and frequencies (monthly/seldom/every day), different therapeutic effects (refractory epilepsy/almost seizure free), normal MRI, and abnormal EEG (epileptiform discharge, slow wave). The phenotypic spectrum with different <i>NPRL3</i> variants was either similar or different. Significantly different relative quantities of mRNA were found between patients and healthy individuals in real-time qPCR. Abnormal splicing was observed in patients compared with healthy individual in RT-PCR. Despite having the same gene variant, different family members had different mRNA splicing, possibly causing different phenotypes.</p><p>Conclusion</p><p>The clinical features of FFEVF varied, and auxiliary inspection was atypical. <i>NPRL3</i>: c.1137dupT could change the relative quantity of mRNA and cause abnormal splicing, which might produce different phenotypes in different family members.</p></div>
Image1_A Novel Loss-of-Function Mutation in the NPRL3 Gene Identified in Chinese Familial Focal Epilepsy with Variable Foci.JPEG
Abstract<p>Familial focal epilepsy with variable foci is an autosomal dominant disorder characterized by partial epilepsy with variable foci. In this study, we report a six-generation with segregation of the mutation present in four generations Chinese family presenting with focal epilepsy with variable foci. Whole exome sequencing confirms a novel pathogenic mutation in the NPRL3 gene (c316C>T; p. Q106*). PCR, Western blotting, and immunohistochemistry were conducted to analyze the gene transcription, protein expression, and subcellular localization of NPRL3 and related signaling molecules in peripheral blood cells from family members. As compared with healthy family members, both mRNA level and protein expression of NPRL3 are decreased in peripheral blood cells of the mutation carrier. In addition, the expression of downstream molecular Phospho-p70 S6 kinase (P-s6k) are increased consequently. Our findings expand the genotypic and phenotypic spectrum of the NPRL3-associated epilepsy and reveal the mechanisms of mTOR pathway signaling and GATOR1 pathogenesis in focal epilepsies, providing exciting potential for future diagnostic and therapeutic interventions. However, further in vitro and animal experiments are still needed to evaluate the role of NPRL3 loss-of-function mutation in epileptogensis.</p>
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.
