DeCure's autonomous Neuro AI scientist is researching a drug-repurposing hypothesis for Charcot-Marie-Tooth disease type 2B2 — 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 moduleCharcot-Marie-Tooth disease type 2B2 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 charcot-marie-tooth disease type 2b2 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
polynucleotide kinase 3'-phosphatase (PNKP) — PNKP 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 2BRF · 1.4 Å · ligand none (apo structure). Experimental structure, not a prediction.
What the evidence adds up to
Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system, with an estimated prevalence of 1 in 1214 persons in the general population of eastern Akershus County, Norway. In that population-based survey of 245 affected individuals from 116 families, CMT type 1 and CMT type 2 were found in 48.2% and 49.4% of families respectively, with intermediate CMT in 2.4%. A mutation in one of the screened genes (PMP22, Cx32, MPZ, MFN2, EGR2, SIMPLE) was found in 27.2% of families and 28.6% of affected individuals. The PMP22 duplication accounted for 13.6% of families and 19.6% of affected individuals; Cx32 mutations for 6.2% of families and 4.8% of affected; MFN2 point mutations for 6.2% of families and 3.2% of affected; and MPZ mutations for 1.2% of families and 1.1% of affected. No point mutations, insertions or deletions were found in EGR2, PMP22 or SIMPLE. The ratio of probable de novo mutations in CMT families was estimated at 22.7%.
MFN2 point mutations, previously thought exclusive to CMT2 and a single intermediate CMT family, were identified in 3.4% (8/232) of unrelated Norwegian CMT families. The associated phenotypes included CMT1 in two families, CMT2 in four, intermediate CMT in one, and distal hereditary motor neuronopathy in one. This expands the clinical spectrum of MFN2 mutations beyond CMT2, but the authors note that further studies are needed to confirm that MFN2 mutations can cause CMT1 and dHMN. A 2025 case report describes a patient with CMT2A carrying the c.1091G>C (p.Arg364Pro) missense mutation in MFN2, illustrating the phenotypic heterogeneity of this subtype.
Two novel MPZ missense mutations were identified: c.368G>A (Gly123Asp) in one family with early-onset severe symptoms compatible with Dejerine-Sottas syndrome, and c.103G>A (Asp35Asn) in two families with late-onset, milder axonal neuropathy compatible with CMT2. Two novel connexin32 mutations causing early-onset X-linked CMT were also found: a deletion c.225delG (R75fsX83) and a c.536G>A (Cys179Tyr) transition disrupting a disulfide bridge. Mean age at onset was in the first decade, with nerve conduction velocities in the intermediate range. An older study of a family with sex-linked CMT found no linkage to the Xg(a) blood group locus and reported abnormal serum alkaline phosphatase levels in both affected and unaffected members.
At present, 47 hereditary neuropathy genes are known, but examination of all known genes would probably identify mutations in only about 50% of CMT cases, suggesting that at least 30–50 CMT genes remain unidentified. The 2011 review notes that the genetic heterogeneity of CMT makes it difficult to determine the subtype without focused genetic testing. What is still missing is a comprehensive genetic test covering all known and yet-to-be-discovered CMT genes, large-scale population-based studies outside Norway to confirm prevalence estimates, and a clearer understanding of how specific mutations produce the wide phenotypic variation seen even within the same gene.
Evidence
Retrieved by DeepSearch across 234,678,978 indexed works and resolved on OpenAlex — ranked by citations, including the results that did not work.
Genetic epidemiology of Charcot-Marie-Tooth disease
AbstractBACKGROUND: Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system. The frequency of different CMT genotypes has been estimated in clinic populations, but prevalence data from the general population is lacking. Point mutations in the mitofusin 2 (MFN2) gene has been identified exclusively in Charcot-Marie-Tooth disease type 2 (CMT2), and in a single family with intermediate CMT. MFN2 point mutations are probably the most common cause of CMT2. The CMT phenotype caused by mutation in the myelin protein zero (MPZ) gene varies considerably, from early onset and severe forms to late onset and milder forms. The mechanism is not well understood. The myelin protein zero (P(0) ) mediates adhesion in the spiral wraps of the Schwann cell's myelin sheath. X-linked Charcot-Marie Tooth disease (CMTX) is caused by mutations in the connexin32 (cx32) gene that encodes a polypeptide which is arranged in hexameric array and form gap junctions. AIMS: Estimate prevalence of CMT. Estimate frequency of Peripheral Myelin Protein 22 (PMP22) duplication and point mutations, insertions and deletions in Cx32, Early growth response 2 (EGR2), MFN2, MPZ, PMP22 and Small integral membrane protein of lysosome/late endosome (SIMPLE) genes. Description of novel mutations in Cx32, MFN2 and MPZ. Description of de novo mutations in MFN2. MATERIAL AND METHODS: Our population based genetic epidemiological survey included persons with CMT residing in eastern Akershus County, Norway. The participants were interviewed and examined by one geneticist/neurologist, and classified clinically, neurophysiologically and genetically. Two-hundred and thirty-two consecutive unselected and unrelated CMT families with available DNA from all regions in Norway were included in the MFN2 study. We screened for point mutations in the MFN2 gene. We describe four novel mutations, two in the connexin32 gene and two in the MPZ gene. RESULTS: A total of 245 affected from 116 CMT families from the general population of eastern Akershus county were included in the genetic epidemiological survey. In the general population 1 per 1214 persons (95% CI 1062-1366) has CMT. Charcot-Marie-Tooth disease type 1 (CMT1), CMT2 and intermediate CMT were found in 48.2%, 49.4% and 2.4% of the families, respectively. A mutation in the investigated genes was found in 27.2% of the CMT families and in 28.6% of the affected. The prevalence of the PMP22 duplication and mutations in the Cx32, MPZ and MFN2 genes was found in 13.6%, 6.2%, 1.2%, 6.2% of the families, and in 19.6%, 4.8%, 1.1%, 3.2% of the affected, respectively. None of the families had point mutations, insertions or deletions in the EGR2, PMP22 or SIMPLE genes. Four known and three novel mitofusin 2 (MFN2) point mutations in 8 unrelated Norwegian CMT families were identified. The novel point mutations were not found in 100 healthy controls. This corresponds to 3.4% (8/232) of CMT families having point mutations in MFN2. The phenotypes were compatible with CMT1 in two families, CMT2 in four families, intermediate CMT in one family and distal hereditary motor neuronopathy (dHMN) in one family. A point mutation in the MFN2 gene was found in 2.3% of CMT1, 5.5% of CMT2, 12.5% of intermediate CMT and 6.7% of dHMN families. Two novel missense mutations in the MPZ gene were identified. Family 1 had a c.368G>A (Gly123Asp) transition while family 2 and 3 had a c.103G>A (Asp35Asn) transition. The affected in family 1 had early onset and severe symptoms compatible with Dejerine-Sottas syndrome (DSS), while affected in family 2 and 3 had late onset, milder symptoms and axonal neuropathy compatible with CMT2. Two novel connexin32 mutations that cause early onset X-linked CMT were identified. Family 1 had a deletion c.225delG (R75fsX83) which causes a frameshift and premature stop codon at position 247 while family 2 had a c.536G>A (Cys179Tyr) transition which causes a change of the highly conserved cysteine residue, i.e. disruption of at least one of three disulfide bridges. The mean age at onset was in the first decade and the nerve conduction velocities were in the intermediate range. DISCUSSION: Charcot-Marie-Tooth disease is the most common inherited neuropathy. At present 47 hereditary neuropathy genes are known, and an examination of all known genes would probably only identify mutations in approximately 50% of those with CMT. Thus, it is likely that at least 30-50 CMT genes are yet to be identified. The identified known and novel point mutations in the MFN2 gene expand the clinical spectrum from CMT2 and intermediate CMT to also include possibly CMT1 and the dHMN phenotypes. Thus, genetic analyses of the MFN2 gene should not be restricted to persons with CMT2. The phenotypic variation caused by different missense mutations in the MPZ gene is likely caused by different conformational changes of the MPZ protein which affects the functional tetramers. Severe changes of the MPZ protein cause dysfunctional tetramers and predominantly uncompacted myelin, i.e. the severe phenotypes congenital hypomyelinating neuropathy and DSS, while milder changes cause the phenotypes CMT1 and CMT2. The two novel mutations in the connexin32 gene are more severe than the majority of previously described mutations possibly due to the severe structural change of the gap junction they encode. CONCLUSION: Charcot-Marie-Tooth disease is the most common inherited disorder of the peripheral nervous system with an estimated prevalence of 1 in 1214. CMT1 and CMT2 are equally frequent in the general population. The prevalence of PMP22 duplication and of mutations in Cx32, MPZ and MFN2 is 19.6%, 4.8%, 1.1% and 3.2%, respectively. The ratio of probable de novo mutations in CMT families was estimated to be 22.7%. Genotype- phenotype correlations for seven novel mutations in the genes Cx32 (2), MFN2 (3) and MPZ (2) are described. Two novel phenotypes were ascribed to the MFN2 gene, however further studies are needed to confirm that MFN2 mutations can cause CMT1 and dHMN.
AbstractCharcot-Marie-Tooth disease (CMT) encompasses the heritable motor and sensory neuropathies that comprise most of the inherited peripheral neuropathies. Due to the great genetic heterogeneity of the condition, it can be difficult to determine what type of CMT a person has. The major phenotypic features of the CMT subtypes are delineated, as well as recommendations for focused genetic testing.
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.
S S Korsakov Journal of Neurology and Psychiatry · 2025 · 0 citations
Phenotypic heterogeneity of Charcot–Marie–Tooth type 2A disease associated with the c.1091G>C missense mutation (p.Arg364Pro) in the MFN2 gene
AbstractCharcot–Marie–Tooth disease belongs to the group of genetically and phenotypically heterogeneous sensory-motor polyneuropathies. Charcot–Marie–Tooth disease type 2A (CMT2A) is the most common axonal form of the disease caused by mutations in the mitofusin-2 gene (MFN2). More than 100 missense mutations in this gene have been registered to date. Many studies have demonstrated the variability of clinical presentation depending on the specific localization of the substitution. The presented clinical case shows the peculiarities of the phenotype of a patient with CMT2A disease associated with the c.1091G>C (p.Arg364Pro) missense mutation in the MFN2 gene.
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.
