DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for paroxysmal extreme pain disorder — screening already-approved drugs against its 2-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleParoxysmal extreme pain disorder maps to a 2-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 paroxysmal extreme pain disorder 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
isocitrate dehydrogenase (NADP(+)) 1 (IDH1) — IDH1 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 ictdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 6BKX · 1.65 Å · ligand ISOCITRIC ACID (ICT). Experimental structure, not a prediction.
What the evidence adds up to
Paroxysmal extreme pain disorder is an autosomal dominant sodium channelopathy caused by mutation of the SCN9A gene. In a 2007 international consortium study, 77 individuals from 15 families were identified. Onset is in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate initially, with skin flushing in all affected individuals and harlequin colour change and tonic attacks in most. Dramatic syncopes with bradycardia and sometimes asystole are common. Later, the disorder is characterised by attacks of excruciating deep burning pain often in the rectal, ocular, or jaw areas, but also diffuse. Attacks are triggered by factors such as defecation, cold wind, eating, and emotion. Carbamazepine is effective in almost all who try it, but the response is often incomplete.
A 2017 report describes a novel SCN9A mutation (heterozygous c.4880T>G substitution) in a 7-month-old child who suffered from typical attacks from birth onwards and whose pain was carbamazepine-resistant. The same mutation was reported again in a 2015 paper. This carbamazepine-resistant phenotype is distinct from the majority of cases, where carbamazepine provides relief. No other drugs are reported as effective in the abstracts. A 2010 case report notes that the condition may be associated with cardiovascular instability and thus has anaesthetic implications, but does not report any new treatment data.
What is still missing is a systematic trial of alternative sodium channel blockers for the carbamazepine-resistant subset, functional characterisation of the c.4880T>G mutation to confirm its pathogenic mechanism, and any clinical trial data at all beyond case reports and small family series. No randomised controlled trial has been conducted, no patient stratification by genotype has been prospectively tested, and no funding for such work is mentioned in these abstracts.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
AbstractOBJECTIVE: To describe the clinical phenotype of paroxysmal extreme pain disorder (previously called familial rectal pain syndrome), an autosomal dominant condition recently shown to be a sodium channelopathy involving SCN9A. METHODS: An international consortium of clinicians, scientists, and affected families was formed. Clinical details of all accessible families worldwide were collected, including age at onset, features of attacks, problems between attacks, investigational results, treatments tried, and evolution over time. A validated pain questionnaire was completed by 14 affected individuals. RESULTS: Seventy-seven individuals from 15 families were identified. The onset of the disorder is in the neonatal period or infancy and persists throughout life. Autonomic manifestations predominate initially, with skin flushing in all and harlequin color change and tonic attacks in most. Dramatic syncopes with bradycardia and sometimes asystole are common. Later, the disorder is characterized by attacks of excruciating deep burning pain often in the rectal, ocular, or jaw areas, but also diffuse. Attacks are triggered by factors such as defecation, cold wind, eating, and emotion. Carbamazepine is effective in almost all who try it, but the response is often incomplete. CONCLUSIONS: Paroxysmal extreme pain disorder is a highly distinctive sodium channelopathy with incompletely carbamazepine-sensitive bouts of pain and sympathetic nervous system dysfunction. It is most likely to be misdiagnosed as epilepsy and, particularly in infancy, as hyperekplexia and reflex anoxic seizures.
Anesthesia for a Patient with Paroxysmal Extreme Pain Disorder
AbstractParoxysmal extreme pain disorder is a very rare condition featured by flushing of the lower half of the body and excruciating burning pain caused by any stimulus below the waist or in the perianal region. It may be associated with cardiovascular instability, and thus has anesthetic implications. This condition is well described in neurological literature, but to our knowledge, this is the first case report of a patient with paroxysmal extreme pain disorder requiring anesthesia for a surgical procedure.
Neonatal and Pediatric Medicine · 2017 · 1 citations · open access
A Novel SCN9A Gene Mutation in a Patient with Carbamazepine-Resistant Paroxysmal Extreme Pain Disorder
AbstractParoxysmal extreme pain disorder is an autosomal dominant disorder caused by mutation of the SCN9A gene. In most cases, the pain is relieved by carbamazepine. We report on a novel SCN9A mutation associated with carbamazepine-resistant. The proband was a 7-month-old child who suffered from typical attacks from birth onwards. Sequencing of SCN9A revealed a heterozygous c.4880T>G substitution. Identification of this novel mutation and characterization of the associated carbamazepine-resistant phenotype may facilitate diagnosis and drug development.
Journal of Pediatric Neurological Disorders · 2015 · 0 citations · open access
A Novel SCN9A Gene Mutation in a Patient with Carbamazepine-ResistantParoxysmal Extreme Pain Disorder
AbstractParoxysmal extreme pain disorder is an autosomal dominant disorder caused by mutation of the SCN9A gene. In most cases, the pain is relieved by carbamazepine. We report on a novel SCN9A mutation associated with carbamazepine-resistant. The proband was a 7-month-old child who suffered from typical attacks from birth onwards. Sequencing of SCN9A revealed a heterozygous c.4880T>G substitution. Identification of this novel mutation and characterization of the associated carbamazepine-resistant phenotype may facilitate diagnosis and drug development.
Selected clinical syndromes of genetic variability in pain sensation
AbstractPain sensation is variable both in animals and humans. Factors that influence the threshold and intensity of pain include race, ethnic origin, sex, material standard of living, stress exposure, environmental conditions and genetic factors. Methods used to identify potential gene variants responsible for the development of pain syndromes include identification of mutation or single nucleotide polymorphism (SNP), analysis of genetic variability in twins, and recently, genome wide association study (GWAS). Pain sensation disorders are the result of a single mutation, as in Biemond syndrome (congenital analgesia), erythromelalgia and paroxysmal extreme pain disorder, or polygenic mutations, as in fibromyalgia and migraine. Sensation of pain starts when the stimulus acts through chemical mediators to activate nerve endings. The signal is then transduced through neurons and spinal pathways to the brain. This process involves synaptic neurotransmitters, membrane receptors, neuromodulators and cell structures that ultimately affect the intensity of pain. The objective of this paper is to present selected clinical syndromes of genetically determined pain sensation disorders and the use of genetic diagnostics in explaining their cause.
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.
