Neuro Lab · DeCure for X
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for Charcot-Marie-Tooth disease type 4C — 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.
No approved-drug candidate for charcot-marie-tooth disease type 4c 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.
Exome sequencing identified a novel TRPV4 mutation in a CMT2C family, but the abstract provides no clinical outcomes or treatment data. A 2007 review notes that rapid advances in molecular genetics have highlighted the great genetic complexity of Charcot-Marie-Tooth disease, and that the evolution from a simple clinical classification to a complex molecular one has not facilitated understanding of the disease. The review also states that different mutations of the same gene produce a range of phenotypes, and that clinicians must look for specific clinical and electrophysiological clues to direct genetic testing.
A 2023 retrospective study of 64 patients with suspected Charcot-Marie-Tooth disease used multiplex ligation probe amplification, next-generation sequencing, and whole-exome sequencing. Twenty-five patients (39%) were diagnosed by multiplex ligation probe amplification. Of 50 patients who underwent next-generation sequencing for targeted gene panels, 18 (36%) had pathogenic or likely pathogenic variants. Whole-exome sequencing on five patients with normal next-generation sequencing results had a diagnostic yield of 80%, higher in the childhood group. The study concludes that patients without a molecular diagnosis in all the literature suggest new genes or mechanisms waiting to be discovered.
A 2011 paper describes the development of the Charcot-Marie-Tooth disease Pediatric Scale (CMTPedS), a multidimensional scale to measure disease severity in children. All items exhibited good to excellent inter-rater reliability (ICC2,4 0.78-0.99). A multicenter natural history study of children aged 3-17 years was underway with 90 children recruited. The authors planned to apply the final CMTPedS as the primary outcome in clinical trials of podiatric, pharmacological and surgical interventions. A 2019 study of a family of six with Charcot-Marie-Tooth phenotypes found that the Reticulon 4 gene was not involved in causing Charcot-Marie-Tooth disease type 1.
No drug treatment is tested or recommended in any of these abstracts. What is still missing is any clinical trial of a pharmacological intervention for CMT4C specifically, validated outcome measures for adult patients, and a molecular diagnosis for a substantial proportion of patients, suggesting that undiscovered genes or mechanisms remain.
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
AbstractMutations in over 50 genes have been associated with Charcot-Marie-Tooth (CMT) disease. As new genes continue to be discovered, the task of sequencing each of them individually with traditional techniques becomes increasingly burdensome. In addition, these approaches have disadvantages that may
https://doi.org/10.1212/wnl.0b013e31825f04b2AbstractPURPOSE OF REVIEW: The purpose of this review is to help neurologists understand new concepts in hereditary neuropathies, from the clinician's point of view, in the molecular era after the burst of information regarding peripheral nerve biology. RECENT FINDINGS: Recent studies have focused on understanding the pathomechanisms involved in hereditary neuropathies. In the past year identification of new genes has slowed down since scientists have concentrated more on the function of genes causing Charcot-Marie-Tooth disease and Schwann cell-axon interactions to reveal the molecular cell biology of the disease. Animal models for the most common subtypes of human Charcot-Marie-Tooth disease are now available. SUMMARY: Rapid advances in the molecular genetics and cell biology of hereditary neuropathies have highlighted the great genetic complexity of Charcot-Marie-Tooth disease. The evolution from a simple clinical classification to a complex molecular one has not facilitated our understanding of the disease. Moreover, the new molecular classification is not simple to use as different mutations of the same gene produce a range of phenotypes. The clinicians have to look for specific clinical and electrophysiological clues to direct the patient to appropriate genetic testing.
https://doi.org/10.1097/wco.0b013e32826fbcb7AbstractOBJECTIVE: 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.
https://doi.org/10.1590/1806-9282.20220929AbstractCharcot-Marie-Tooth disease (CMT) causes peripheral nerve demyelination, progressive foot weakness, cavus deformity, difficulty walking and sensory loss. There is a need for accurate, sensitive and disease-relevant measures of young children through to adolescents with CMT to enable accurate assessment of baseline performance, monitor disease severity longitudinally, and determine responses to existing and novel foot and ankle interventions. Our objective was to develop a multidimensional scale to measure disease severity of children with CMT, known as the CMT Pediatric Scale (CMTPedS). The CMTPedS has undergone a thorough development process: (1) definition of the construct; (2) generation of the item pool; (3) choice of scoring format; (4) peer-review (face validity); (5) pilot testing; (6) standardised training; (7) inter-rater reliability of four international centres assessing eight children with CMT; (8) multicenter implementation. Findings of the development process: (1) the CMTPedS is a composite scale with broad application to measure disease severity of childhood CMT with eight domains capturing symptoms, foot/ankle involvement, lower limb sensation, hand dexterity/strength, balance, motor function; (2) a large pool of items generated from the literature were reduced based on disease-specificity, functional/patient-relevance, reliability/validity, published norms, test duration and ease of interpretation; (3) items collapsed to 5-point Likert scales using z-scores based on age/gender norms; (4) quality, appropriateness and suitability of items peer-reviewed by 23 expert clinicians/researchers/patient representatives at the 168th European Neuromuscular Centre International Workshop; (5) pilot-tested on four children with CMT to check for administration problems, item instructions, order and duration; (6) clinicians from USA, UK, Italy and Australia trained through workshops, online manual and video resources; (7) all items exhibited good to excellent inter-rater reliability (ICC2,40.78-0.99) (8) a multicenter natural history study of children with all types of CMT aged 3-17 years is underway, with 90 children recruited to date. Application and psychometric validation of the CMTPedS continues. We plan to apply the final CMTPedS as the primary outcome in clinical trials of podiatric, pharmacological and surgical interventions.
https://doi.org/10.1186/1757-1146-4-s1-o12AbstractOBJECTIVES: To find interactions of the ligand with axonali nhibitors, and to check the optimum interactions of existing drugs as inhibitors for the protein that hinders the growth of injured neurons. METHODS: The study was conducted at Kongju National University, Korea from May 2016 to March 2017. It consisted of two parts. Molecular analysis and bioinformatics analysis. The study comprised a family of six with Charcot-Marie-Tooth phenotypes, recommended by a neurologist for molecular analysis on the clinical symptoms to find the mutations responsible for the disease. Blood samples were collected from each family member and total deoxyribonucleic acid was extracted and it was analysed for Reticulon 4 gene by sequencing the coding and intronic regions. However, a missense mutation was found on exon 2 of the gene in the proband and the whole family was subsequently analysed. Bioinformatics analysis and docking studies were carried out to investigate the potential behaviour of Reticulon 4 as therapeutic agent. Sequencing analysis was performed to find the pathoegenic variant responsible for Charcot-Marie-Tooth type 1. RESULTS: After checking pathogenicity of the mutation, Reticulon 4 gene was found to be not involved in Charcot- Marie-Tooth disease type 1. CONCLUSIONS: Reticulon 4 gene was not found to be involved in causing Charcot-Marie-Tooth disease type 1.
https://doi.org/10.5455/jpma.275388Disease 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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