DeCure for Charcot-Marie-Tooth disease X-linked dominant 1
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for Charcot-Marie-Tooth disease X-linked dominant 1 — screening already-approved drugs against its 5-gene Open Targets disease module to publish open-access research. Research is fast; the path to publication is funded in milestone stages.
Disease moduleCharcot-Marie-Tooth disease X-linked dominant 1 maps to a 5-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 charcot-marie-tooth disease x-linked dominant 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
sacsin molecular chaperone (SACS) — SACS 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 5V44 · 1.56 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
In a geographically defined Mediterranean area, molecular diagnosis was achieved in 365 of 438 patients (83.3%) with Charcot-Marie-Tooth disease. The CMT1A duplication of the PMP22 gene accounted for 50.4% of diagnoses, followed by mutations in GJB1 (15.3%) and GDAP1 (11.5%). Mutations in MFN2 were found in only 1.1% of cases, and recessive inheritance was observed in 11.6%. Sixteen novel mutations were identified and phenotypically characterised. In a separate retrospective study using multiplex ligation probe amplification, next-generation sequencing, and whole-exome sequencing, 25 of 64 patients (39%) were diagnosed by multiplex ligation probe amplification. Among 50 patients who underwent targeted gene panels, 18 (36%) had pathogenic or likely pathogenic variants. Whole-exome sequencing on five patients with normal panel results gave an 80% diagnostic yield, higher in the childhood group. The authors note that patients without a molecular diagnosis persist across the literature, suggesting undiscovered genes or mechanisms.
A family with X-linked Charcot-Marie-Tooth disease showed irregular dominant sex-linked inheritance. No linkage was established between the Xg(a) blood group locus and the CMT locus. Abnormal serum alkaline phosphatase levels were found in both affected and unaffected family members. A second family harbouring the MFN2 c.2222T>G (p.Leu741Trp) mutation confirmed its pathogenicity, but disease onset in this family was much later than in previously reported cases, indicating variable expressivity.
More than 90 causative genes for Charcot-Marie-Tooth disease have been identified. The disease is divided into subtypes including CMT1, CMT2, CMT3, CMT4, CMT5, CMT6, X-linked CMT, and intermediate CMT. Animal studies have reported molecules with therapeutic effects on specific subtypes depending on the underlying genetic cause, and induced pluripotent stem cell research has expanded possibilities for patient-specific cell therapy and drug discovery. Accurate genetic diagnosis is considered crucial for any future customised therapy.
What is still missing is a therapy that has been shown to alter the course of any CMT subtype in controlled human trials. The genetic heterogeneity means that a single drug is unlikely to work across all forms, yet most preclinical work remains in animal models. Stratification by specific mutation, age at onset, and inheritance pattern will be needed for any trial design, and funding for such stratified trials remains scarce.
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 · 2013 · 131 citations · open access
Charcot-Marie-Tooth disease
AbstractOBJECTIVES: To determine the genetic distribution and the phenotypic correlation of an extensive series of patients with Charcot-Marie-Tooth disease in a geographically well-defined Mediterranean area. METHODS: A thorough genetic screening, including most of the known genes involved in this disease, was performed and analyzed in this longitudinal descriptive study. Clinical data were analyzed and compared among the genetic subgroups. RESULTS: Molecular diagnosis was accomplished in 365 of 438 patients (83.3%), with a higher success rate in demyelinating forms of the disease. The CMT1A duplication (PMP22 gene) was the most frequent genetic diagnosis (50.4%), followed by mutations in the GJB1 gene (15.3%), and in the GDAP1 gene (11.5%). Mutations in 13 other genes were identified, but were much less frequent. Sixteen novel mutations were detected and characterized phenotypically. CONCLUSIONS: The relatively high frequency of GDAP1 mutations, coupled with the scarceness of MFN2 mutations (1.1%) and the high proportion of recessive inheritance (11.6%) in this series exemplify the particularity of the genetic distribution of Charcot-Marie-Tooth disease in this region.
Charcot-Marie-Tooth Disease with Sex-Linked Inheritance, Linkage Studies and Abnormal Serum Alkaline Phosphatase Levels
AbstractA family with Charcot-Marie-Tooth disease (CMT) is described. An irregular dominant sex-linked inheritance is observed. No linkage relationship between the Xg(a) blood group locus and the CMT locus was established. Abnormal values of the serum alkaline phosphatase level were found in affected and unaffected members.
Precision and Future Medicine · 2019 · 24 citations · open access
Clinical and genetic aspects of Charcot-Marie-Tooth disease subtypes
AbstractCharcot-Marie-Tooth disease (CMT) is one of the most common inherited neuropathies and is both genetically and clinically heterogeneous, with variable inheritance modes. With regard to clinical and genetic aspects, CMT is divided into several subtypes, including CMT1, CMT2, CMT3, CMT4, CMT5, CMT6, X-linked CMT, and intermediate CMT. Up to date, more than 90 causative genes for CMT have been identified. Furthermore, previous animal studies reported some molecules to have therapeutic effects on specific CMT subtypes, depending on the underlying genetic cause. Therefore, accurate genetic diagnosis is of crucial importance when performing customized therapy. Finally, recent investigations on induced pluripotent stem cells expanded the possibility of both patient-specific cell therapy and drug discovery. The current review focuses on the latest classification updates for accurate CMT diagnosis.
Revista da Associação Médica Brasileira · 2023 · 6 citations · open access
High diagnostic yield with algorithmic molecular approach on hereditary neuropathies
AbstractOBJECTIVE: Charcot-Marie-Tooth disease covers a group of inherited peripheral neuropathies. The aim of this study was to investigate the effect of targeted next-generation sequencing panels on the molecular diagnosis of Charcot-Marie-Tooth disease and its subtypes in routine clinical practice, and also to show the limitations and importance of next-generation sequencing in the diagnosis of Charcot-Marie-Tooth diseases. METHODS: This is a retrospective study. Three different molecular methods (multiplex ligation probe amplification, next-generation sequencing, and whole-exome sequencing) were used to detect the mutations related to Charcot-Marie-Tooth disease. RESULTS: In total, 64 patients (33 males and 31 females) with suspected Charcot-Marie-Tooth disease were analyzed for molecular etiology. In all, 25 (39%) patients were diagnosed by multiplex ligation probe amplification. With an extra 11 patients with normal PMP22 multiplex ligation probe amplification results that were consulted to our laboratory for further genetic analysis, a total of 50 patients underwent next-generation sequencing for targeted gene panels associated with Charcot-Marie-Tooth disease. Notably, 18 (36%) patients had pathogenic/likely pathogenic variants. Whole-exome sequencing was performed on five patients with normal next-generation sequencing results; the diagnostic yield by whole-exome sequencing was 80% and it was higher in the childhood group. CONCLUSION: The molecular etiology in Charcot-Marie-Tooth disease patients can be determined according to pre-test evaluation, deciding the inheritance type with pedigree analysis, the clinical phenotype, and an algorithm for the genetic analysis. The presence of patients without a molecular diagnosis in all the literature suggests that there are new genes or mechanisms waiting to be discovered in the etiology of Charcot-Marie-Tooth disease.
Journal of Neuromuscular Diseases · 2019 · 2 citations
Late onset CMT2A in a Family with an MFN2 Variant: c.2222T>G (p.Leu741Trp)
AbstractMutations in MFN2 cause a range of Charcot-Marie-Tooth disease (CMT) phenotypes with different inheritance patterns and underlying pathogenic mechanisms. Recently, a family with a dominantly inherited CMT harboring c.2222T>G (p.Leu741Trp) mutation in MFN2 has been reported for the first time. Here, we report a second family also with a dominantly inherited CMT harboring the same mutation, thereby confirming the pathogenicity of this mutation. Interestingly, the disease onset of this second family is much later than the previously reported cases.
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.
