DeCure for Charcot-Marie-Tooth disease dominant intermediate E
DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for Charcot-Marie-Tooth disease dominant intermediate E — 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 moduleCharcot-Marie-Tooth disease dominant intermediate E 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 charcot-marie-tooth disease dominant intermediate e 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
inverted formin 2 (INF2) — INF2 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 adpdrag to rotate · scroll to zoom
RCSB Protein Data Bank · entry 9AZP · 3.79 Å · ligand ADENOSINE-5'-DIPHOSPHATE (ADP). Experimental structure, not a prediction.
What the evidence adds up to
In a retrospective diagnostic study of 64 patients with suspected Charcot-Marie-Tooth disease, 25 (39%) were diagnosed by multiplex ligation probe amplification. Among 50 patients who then 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 gave a diagnostic yield of 80%, higher in the childhood group. The authors note that patients without a molecular diagnosis appear in all the literature, suggesting undiscovered genes or mechanisms remain.
A second family with a dominantly inherited CMT harbouring the c.2222T>G (p.Leu741Trp) mutation in MFN2 has been reported, confirming the pathogenicity of this mutation. The disease onset in this second family was much later than in previously reported cases. Separately, sequencing analysis of the Reticulon 4 gene in a family of six with CMT phenotypes found a missense mutation on exon 2 of the gene in the proband, but after checking pathogenicity the Reticulon 4 gene was found not to be involved in causing Charcot-Marie-Tooth disease type 1.
A nationwide population-based study in Korea from 2005 to 2018 enrolled 2,885 CMT patients. The prevalence in 2018 was 5.2 per 100,000 persons (6.1 for men, 4.4 for women), peaking at ages 15–39 years with nearly twice as many men as women in that age group. Of the patients, 7.8% were receiving medical aid at diagnosis and 8.8% at last follow-up or death. From 2005 to 2017, 170 patients died (118 men, 52 women). The standardized mortality ratio was 1.57 (95% CI 1.34–1.83) for all patients, with the highest age-specific ratio in patients under 9 years. Neurologic disease as a cause of death was significantly more frequent in CMT patients than in the general population.
What is still missing for dominant intermediate E specifically is any trial data, any drug tested in patients, and any clear stratification by genetic subtype. The diagnostic studies show that many patients remain without a molecular diagnosis, and the epidemiological data confirm increased mortality and socioeconomic burden, but no interventional study has been reported for this particular CMT form.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
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.
Supplementary Material for: Prevalence, Mortality, and Cause of Death in Charcot-Marie-Tooth Disease in Korea: A Nationwide, Population-Based Study
Abstract<b><i>Background:</i></b> Charcot-Marie-Tooth disease (CMT) is a group of clinically and genetically heterogeneous disorders that primarily affect the peripheral nervous system. Epidemiological studies of CMT have not yet been performed in Korea. <b><i>Objectives:</i></b> This study was performed to estimate the prevalence of CMT in Korea and the socioeconomic status, mortality, and causes of death of Korean patients with CMT. <b><i>Methods:</i></b> Data on patients with CMT were obtained from the rare intractable disease registry and the National Health Insurance Service for the years 2005–2018. <b><i>Results:</i></b> During the study period, 2,885 CMT patients were enrolled. The prevalence per 100,000 persons in 2018 was 5.2 (6.1 for men and 4.4 for women), peaking at ages 15–39 years, with almost twice as many men (<i>n</i> = 714) as women (<i>n</i> = 402) in this age group. Of the CMT patients, 226 (7.8%) were receiving medical aid, a public assistance program targeting poor individuals, at the time of diagnosis and 253 (8.8%) at last follow-up or death. From 2005 to 2017, 170 patients died, including 118 men and 52 women. The standardized mortality ratio (SMR) was 1.57 (95% CI 1.34–1.83) for all patients and did not differ in men and women. Age-specific SMR was highest in patients aged under 9 years, gradually declining thereafter. Neurologic disease as a cause of death was significantly more frequent in CMT patients than in the general population. <b><i>Conclusions:</i></b> This was the first nationwide epidemiologic study of CMT patients in Korea. This study confirmed the characteristics associated with the prevalence of and mortality from CMT by age and is the first to report the socioeconomic status and causes of death of CMT patients.
Supplementary Material for: Prevalence, Mortality, and Cause of Death in Charcot-Marie-Tooth Disease in Korea: A Nationwide, Population-Based Study
Abstract<b><i>Background:</i></b> Charcot-Marie-Tooth disease (CMT) is a group of clinically and genetically heterogeneous disorders that primarily affect the peripheral nervous system. Epidemiological studies of CMT have not yet been performed in Korea. <b><i>Objectives:</i></b> This study was performed to estimate the prevalence of CMT in Korea and the socioeconomic status, mortality, and causes of death of Korean patients with CMT. <b><i>Methods:</i></b> Data on patients with CMT were obtained from the rare intractable disease registry and the National Health Insurance Service for the years 2005–2018. <b><i>Results:</i></b> During the study period, 2,885 CMT patients were enrolled. The prevalence per 100,000 persons in 2018 was 5.2 (6.1 for men and 4.4 for women), peaking at ages 15–39 years, with almost twice as many men (<i>n</i> = 714) as women (<i>n</i> = 402) in this age group. Of the CMT patients, 226 (7.8%) were receiving medical aid, a public assistance program targeting poor individuals, at the time of diagnosis and 253 (8.8%) at last follow-up or death. From 2005 to 2017, 170 patients died, including 118 men and 52 women. The standardized mortality ratio (SMR) was 1.57 (95% CI 1.34–1.83) for all patients and did not differ in men and women. Age-specific SMR was highest in patients aged under 9 years, gradually declining thereafter. Neurologic disease as a cause of death was significantly more frequent in CMT patients than in the general population. <b><i>Conclusions:</i></b> This was the first nationwide epidemiologic study of CMT patients in Korea. This study confirmed the characteristics associated with the prevalence of and mortality from CMT by age and is the first to report the socioeconomic status and causes of death of CMT patients.
Journal of the Pakistan Medical Association · 2019 · 0 citations · open access
In-silico and Molecular Analysis of RTN4 as novel therapeutic option for axonal regeneration
AbstractOBJECTIVES: 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.
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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