DeCure's autonomous Rare AI scientist is researching a drug-repurposing hypothesis for congenital myasthenic syndrome 17 — 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 moduleCongenital myasthenic syndrome 17 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 congenital myasthenic syndrome 17 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
LDL receptor related protein 4 (LRP4) — LRP4 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 8S9P · 3.8 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
In 13 families with chromosome 17p-linked congenital myasthenic syndrome, all 37 patients carried homozygous mutations in the acetylcholine receptor ε-subunit gene. Five novel mutations were identified: two truncating (ε723delC, ε760ins8), two missense (εV-13D in the signal peptide, εT51P in the N-terminal extracellular domain), and one splice donor site mutation in intron 10 (εIVS10+2T→G). Expression studies in human embryonic kidney cells showed that all four coding-region mutations and the most likely transcript of the splice-site mutation (which skips exon 10) are low-expressor or null mutations. Unaffected family members had no mutations or were heterozygous. The authors concluded that chromosome 17p-linked CMS is caused by low-expressor or null mutations in the AChR ε-subunit gene, and that mutations in this gene are a common cause of CMS in eastern Mediterranean countries.
A 2013 report described two siblings with familial limb girdle myasthenia who showed significant objective clinical improvement after initiation of terbutaline. The authors noted that terbutaline is a potential treatment option in certain CMS subtypes refractory to conventional medicines, but that long-term follow-up is required to determine overall efficacy and safety. No controlled trial data, sample sizes beyond these two patients, or response rates were provided.
A 2022 review stated that CMS is a group of partially treatable genetic disorders with more than thirty known pathogenic genes, and that misdiagnosis and missed diagnosis are common. A 2023 guideline supplement for management of myasthenic syndromes was published, but its specific recommendations for CMS 17 are not detailed in the available abstracts.
What is still missing: no randomised controlled trials exist for terbutaline in CMS 17 specifically; the 2013 report involved only two patients with a broader limb girdle phenotype, not genetically confirmed CMS 17. No long-term safety or efficacy data are available. Patient stratification by exact ε-subunit mutation has not been tested in a treatment trial. Funding for a properly powered, genotype-stratified trial is absent.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Neurology · 1999 · 45 citations
Chromosome 17p-linked myasthenias stem from defects in the acetylcholine receptor ε-subunit gene
AbstractOBJECTIVE: To identify and to characterize functionally the mutational basis of congenital myasthenic syndromes (CMS) linked to chromosome 17p. BACKGROUND: A total of 37 patients belonging to 13 CMS families, 9 of them consanguineous, were investigated. All patients were linked previously to the telomeric region of chromosome 17p. Two candidate genes in this region encode synaptobrevin 2, a presynaptic protein, and the epsilon-subunit of the acetylcholine receptor (AChR). Direct sequencing of the synaptobrevin 2 gene revealed no mutations. The authors thus searched for mutations in the epsilon-subunit gene of AChR. METHODS: Direct sequencing of the AChR epsilon-subunit, restriction analysis, allele-specific PCR, and expression studies in human embryonic kidney cells were performed. RESULTS: The authors identified two previously characterized and five novel epsilon-subunit gene mutations, all homozygous, in the 13 kinships. Two of the novel mutations are truncating (epsilon723delC and epsilon760ins8), one is a missense mutation in the signal peptide region (epsilonV-13D), one is a missense mutation in the N-terminal extracellular domain (epsilonT51P), and one is a splice donor site mutation in intron 10 (epsilonIVS10+2T-->G). Unaffected family members have no mutations or are heterozygous. Expression studies indicate that the four novel mutations in the coding region of the gene and the most likely transcript of the splice-site mutation, which skips exon 10, are low-expressor or null mutations. CONCLUSIONS: Chromosome 17p-linked congenital myasthenic syndromes are caused by low-expressor/null mutations in the AChR epsilon-subunit gene. Mutations in this gene are a common cause of CMS in eastern Mediterranean countries.
Two cases of congenital myasthenic syndrome with vocal cord paralysis
AbstractCongenital myasthenic syndrome (CMS) typically presents within the first year of life with fluctuating and fatigable muscle weakness, often affecting ocular and bulbar muscles.1 In spite of bulbar involvement, vocal cord paralysis (VCP) is an uncommon presentation of CMS,2 and is most often seen in peripheral neuropathies such as TRPV4 mutations.3 We report 2 cases of CMS with 2 novel mutations in which VCP was a major sign.
Annals of Indian Academy of Neurology · 2013 · 0 citations · open access
Efficacy of terbutaline in familial limb girdle myasthenia
AbstractCongenital myasthenic syndromes (CMS) are frequently misdiagnosed due to their wide clinical heterogeneity. Molecular defects in various end-plate associated proteins are being identified. Better understanding of the molecular pathogenesis and genotype-phenotype correlations can help evolve newer therapeutic targets. We present a report of two siblings with familial limb girdle myasthenia who showed significant objective clinical improvement after initiation of terbutaline. The possible mechanism of action and utility of terbutaline in the setting of CMS are described. Terbutaline is a potential treatment option in certain subtypes of CMS refractory to conventional medicines. However, long-term follow-up is required to determine the overall efficacy and safety profile.
sj-docx-1-tan-10.1177_17562864231213240 – Supplemental material for Guideline for the management of myasthenic syndromes
AbstractSupplemental material, sj-docx-1-tan-10.1177_17562864231213240 for Guideline for the management of myasthenic syndromes by Heinz Wiendl, Angela Abicht, Andrew Chan, Adela Della Marina, Tim Hagenacker, Khosro Hekmat, Sarah Hoffmann, Hans-Stefan Hoffmann, Sebastian Jander, Christian Keller, Alexander Marx, Arthur Melms, Nico Melzer, Wolfgang Müller-Felber, Marc Pawlitzki, Jens-Carsten Rückert, Christiane Schneider-Gold, Benedikt Schoser, Bettina Schreiner, Michael Schroeter, Bettina Schubert, Jörn-Peter Sieb, Fritz Zimprich and Andreas Meisel in Therapeutic Advances in Neurological Disorders
DOAJ (DOAJ: Directory of Open Access Journals) · 2022 · 0 citations
Congenital Myasthenic Syndrome
AbstractCongenital Myasthenic syndrome (CMS) is a group of partially treatable genetic disorders characterized by dysfunction of neuromuscular junction signaling.With the popularization of high-throughput sequencing and in-depth understanding of the disease in recent years, more than thirty pathogenic genes have been discovered and there is a correlation between genotype and clinical phenotype.Misdiagnosis and missed diagnosis are common in clinical practice. This paper summarized the molecular mechanisms, clinical features, electrophysiologic, pathological features and treatment of main subtypes of CMS to deepen the understanding of the disease.
Recent Advances in Understanding Congenital Myasthenic Syndromes
AbstractCongenital myasthenic syndromes (CMS) are rare genetic disorders that continue to challenge the skills of clinical electrophysiologists, neuromuscular specialists, and general neurologists. Their pathogenesis remained elusive until the early 1990s, when advances in molecular genetics and in vitro neurophysiology of intercostal muscle biopsies provided major insights into disease mechanisms and created new ways to confirm …
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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