| Item | Evidence-backed statement/data | Source (first author, journal, year) | PMID/DOI/URL | Notes for ontology mapping |
|---|---|---|---|---|
| Disease definition | CMT1 is the demyelinating form of Charcot-Marie-Tooth disease, an inherited peripheral neuropathy affecting peripheral nerves/Schwann cells with slowly progressive distal weakness, sensory loss, and foot deformities (pqac-00000001, pqac-00000016) | Okamoto, *Genes*, 2023; Dong, *Biomolecules*, 2024 | DOI: 10.3390/genes14071391; https://doi.org/10.3390/genes14071391; DOI: 10.3390/biom14091138; https://doi.org/10.3390/biom14091138 | MONDO:0019011; UBERON:0000010 peripheral nervous system; CL:0002573 myelinating Schwann cell; HPO: HP:0003401 distal muscle weakness, HP:0009836 peripheral neuropathy |
| Electrophysiologic classification | In one recent treatment review, demyelinating CMT1 is defined by upper-limb MNCV **<38 m/s**, axonal CMT2 by **>38 m/s**, and intermediate forms by **25–45 m/s** (pqac-00000001, pqac-00000002) | Okamoto, *Genes*, 2023; Estévez-Arias, *J Transl Genet Genom*, 2022 | DOI: 10.3390/genes14071391; https://doi.org/10.3390/genes14071391; DOI: 10.20517/jtgg.2022.04; https://doi.org/10.20517/jtgg.2022.04 | HPO support: HP:0003448 reduced nerve conduction velocity |
| Electrophysiologic subclassification | Another 2024 review gives forearm ulnar motor NCV ranges: **very slow <15 m/s; slow 15–35 m/s; intermediate 35–45 m/s; normal >45 m/s** (pqac-00000006, pqac-00000016) | Dong, *Biomolecules*, 2024 | DOI: 10.3390/biom14091138; https://doi.org/10.3390/biom14091138 | Useful for phenotype annotation and diagnostic rule representation |
| Cohort-specific strict CMT1 cutoff | In the large UK diagnostic cohort, CMT1 was operationally defined as demyelinating neuropathy with upper-limb MNCV **<25 m/s** (pqac-00000009, pqac-00000012) | Record, *Brain*, 2024 | DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 | Note cohort definition differs from broader review cutoffs; encode as study-specific diagnostic criterion |
| Prevalence estimate | Recent reviews report CMT prevalence ranging from **1 in 2,500 to 1 in 10,000** individuals (pqac-00000012) | Record, *Brain*, 2024 | DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 | Disease-level epidemiology; aggregated resource, not individual EHR-derived |
| General prevalence estimate | Other recent reviews summarize CMT prevalence as approximately **1:2,500** (pqac-00000002, pqac-00000016) | Estévez-Arias, *J Transl Genet Genom*, 2022; Dong, *Biomolecules*, 2024 | DOI: 10.20517/jtgg.2022.04; https://doi.org/10.20517/jtgg.2022.04; DOI: 10.3390/biom14091138; https://doi.org/10.3390/biom14091138 | Supports common “most prevalent inherited neuropathy” statement |
| Major causal architecture | CMT1A is caused by a recurrent chromosome 17 duplication containing **PMP22**; the canonical lesion is described as a **1.4 Mbp** duplication in recent literature (pqac-00000003, pqac-00000009) | Estévez-Arias, *J Transl Genet Genom*, 2022; Record, *Brain*, 2024 | DOI: 10.20517/jtgg.2022.04; https://doi.org/10.20517/jtgg.2022.04; DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 | MONDO:0007309 CMT1A; gene: PMP22; structural variant/CNV annotation |
| PMP22 share of all CMT | PMP22 duplication/CMT1A accounts for about **50% of all CMT** cases in one review (pqac-00000014) | Estévez-Arias, *J Transl Genet Genom*, 2022 | DOI: 10.20517/jtgg.2022.04; https://doi.org/10.20517/jtgg.2022.04 | Genetic epidemiology fact; useful for testing prioritization |
| PMP22 share of demyelinating CMT | The same review states PMP22 duplication accounts for about **70.7% of demyelinating CMT** (pqac-00000014) | Estévez-Arias, *J Transl Genet Genom*, 2022 | DOI: 10.20517/jtgg.2022.04; https://doi.org/10.20517/jtgg.2022.04 | Apply specifically to CMT1/demyelinating subgroup |
| PMP22 share of solved cases | In the UK specialist cohort, **PMP22 duplication = 505/1165 solved cases (43.3%)** (pqac-00000012) | Record, *Brain*, 2024 | DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 | High-value disease-gene frequency datum |
| PMP22 share within CMT1 | In the same cohort, **505/621 CMT1 cases (82.3%)** had PMP22 duplication; among solved CMT1, this was **84.0%** (pqac-00000010) | Record, *Brain*, 2024 | DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 | Supports first-line PMP22 CNV testing in CMT1 phenotype |
| CMT1 diagnostic rate | In the large UK cohort, genetic diagnosis was achieved in **601/621 CMT1 cases (96.8%)** (pqac-00000010, pqac-00000012) | Record, *Brain*, 2024 | DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 | Disease subclass-specific diagnostic performance metric |
| Overall diagnostic yield | Across 1,515 patients with CMT/related disorders, overall genetic diagnosis was **76.9% (1165/1515)** (pqac-00000009, pqac-00000012) | Record, *Brain*, 2024 | DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 | Real-world implementation metric for specialist inherited neuropathy service |
| Preferred first-line CNV test | The 2024 *Brain* cohort paper states **MLPA remains the preferred test for CMT1A** (pqac-00000009) | Record, *Brain*, 2024 | DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 | Diagnostic ontology note: CNV assay; consider MAXO-like testing action mapping externally |
| WGS diagnostic uplift | In the UK cohort, WGS provided an overall diagnostic uplift of **3.5%** across the whole cohort (pqac-00000012) | Record, *Brain*, 2024 | DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 | Implementation metric for genome sequencing in unsolved neuropathy |
| WGS yield in 100KGP subset | In the UK 100,000 Genomes subset, the “true” WGS diagnostic rate was **19.7% (46/233)** after excluding diagnoses obtained by other means (pqac-00000012) | Record, *Brain*, 2024 | DOI: 10.1093/brain/awae064; https://doi.org/10.1093/brain/awae064 | Useful for expectations after prior routine testing |
| PMP22 overexpression mechanism | PMP22 overexpression in CMT1A leads to **protein aggregates**, reduced proteasome activity, accumulation of insoluble ubiquitinated substrates, and **Schwann-cell apoptosis** (pqac-00000013) | Dong, *Biomolecules*, 2024 | DOI: 10.3390/biom14091138; https://doi.org/10.3390/biom14091138 | GO: protein aggregation, proteasome-mediated ubiquitin-dependent protein catabolic process, apoptotic process; CL: myelinating Schwann cell |
| MPZ/UPR mechanism | For CMT1B, **MPZ** mutations can cause ER retention, activation of the **unfolded protein response (UPR)**, and disruption of myelin compaction (pqac-00000013) | Dong, *Biomolecules*, 2024 | DOI: 10.3390/biom14091138; https://doi.org/10.3390/biom14091138 | GO: response to endoplasmic reticulum stress, unfolded protein response, myelination; UBERON: peripheral nerve |
| Pathobiology theme | Recent mechanistic reviews emphasize Schwann-cell/myelin dysfunction as central to demyelinating CMT, linking dysfunctional myelin to secondary axonal damage and disability (pqac-00000001, pqac-00000003) | Okamoto, *Genes*, 2023; Estévez-Arias, *J Transl Genet Genom*, 2022 | DOI: 10.3390/genes14071391; https://doi.org/10.3390/genes14071391; DOI: 10.20517/jtgg.2022.04; https://doi.org/10.20517/jtgg.2022.04 | GO: myelination, axon ensheathment; CL: Schwann cell; UBERON: peripheral nerve |
| Outcome measure validation sample | The validated **CMT-FOM** was tested in **214 adults with CMT1A**, ages 18–75, **58% female**, across US/UK/Italy sites (pqac-00000017) | Mandarakas, *Neurology*, 2024 | DOI: 10.1212/WNL.0000000000207963; https://doi.org/10.1212/wnl.0000000000207963 | Clinical outcome assessment for trials; supportive of endpoint ontology mapping |
| CMT-FOM structure | The CMT-FOM was validated as a **12-item unidimensional interval scale** with a **0–100** scoring system covering strength, upper/lower limb function, balance, and mobility (pqac-00000017) | Mandarakas, *Neurology*, 2024 | DOI: 10.1212/WNL.0000000000207963; https://doi.org/10.1212/wnl.0000000000207963 | Functional phenotype capture: gait/balance/hand weakness/falls |
| CMT-FOM psychometric correlation 1 | CMT-FOM correlated with the **CMT Examination Score** at **r = 0.643; p < 0.001** (pqac-00000017) | Mandarakas, *Neurology*, 2024 | DOI: 10.1212/WNL.0000000000207963; https://doi.org/10.1212/wnl.0000000000207963 | Trial-readiness metric |
| CMT-FOM psychometric correlation 2 | CMT-FOM correlated with the **Overall Neuropathy Limitation Scale** at **r = 0.516; p < 0.001** (pqac-00000017) | Mandarakas, *Neurology*, 2024 | DOI: 10.1212/WNL.0000000000207963; https://doi.org/10.1212/wnl.0000000000207963 | Endpoint harmonization with prior CMT trials |
| PXT3003 Phase III design (PLEO-CMT) | **NCT02579759** enrolled **323** patients in a randomized, double-blind, placebo-controlled phase III trial; primary endpoint was **ONLS total score** averaged from months 12 and 15 (pqac-00000020) | ClinicalTrials.gov NCT02579759, 2015 registration | https://clinicaltrials.gov/study/NCT02579759 | MAXO suggestion: combination pharmacotherapy; disease-modifying investigational treatment |
| PXT3003 Phase III secondary endpoints (PLEO-CMT) | PLEO-CMT key secondary endpoints included **10MWT, CMTNS-v2 sensory/exam scores, 9-HPT**, plus safety outcomes (TEAEs, withdrawals, SAEs) (pqac-00000020) | ClinicalTrials.gov NCT02579759, 2015 registration | https://clinicaltrials.gov/study/NCT02579759 | Endpoint catalog for trial knowledge base |
| PLEO-CMT notable event | In PLEO-CMT, the high-dose arm was prematurely discontinued on **18 Sep 2017** because of a **product quality/stability** issue; the DSMC had **not identified safety concerns** (pqac-00000020) | ClinicalTrials.gov NCT02579759, 2015 registration | https://clinicaltrials.gov/study/NCT02579759 | Important for interpreting phase III efficacy evidence |
| PXT3003 Phase III design (PREMIER) | **NCT04762758** is a multicenter randomized placebo-controlled phase III study planning about **350** subjects, with **mONLS** and **10-Meter Walk Test** as primary outcomes at **Month 15** (pqac-00000019) | ClinicalTrials.gov NCT04762758, 2021 registration | https://clinicaltrials.gov/study/NCT04762758 | MAXO suggestion: oral combination drug therapy |
| PXT3003 Phase III dosing (PREMIER) | In PREMIER, PXT3003 is given **10 mL twice daily** for **15 months** after a **2-week half-dose titration** (5 mL BID) (pqac-00000019) | ClinicalTrials.gov NCT04762758, 2021 registration | https://clinicaltrials.gov/study/NCT04762758 | Administration detail for intervention annotation |
| PXT3003 phase III status | PREMIER was reported as **ACTIVE_NOT_RECRUITING** at last update in the registry excerpt (pqac-00000019) | ClinicalTrials.gov NCT04762758, 2021 registration | https://clinicaltrials.gov/study/NCT04762758 | Current implementation status; check registry for latest changes |
| Additional phase III registry | A separate phase III PXT3003 study, **NCT05092841**, is listed in trial search results as **completed** with **176** participants (pqac-00000000) | ClinicalTrials.gov search results, 2024 retrieval | https://clinicaltrials.gov/study/NCT05092841 | Registry-level fact only from retrieved trial metadata |
| Visual diagnostic aid | A recent review contains a figure showing typical CMT phenotypes (**claw hands, pes cavus**) and a table classifying demyelinating/intermediate/axonal CMT by NCV thresholds (pqac-00000021) | Dong, *Biomolecules*, 2024 | DOI: 10.3390/biom14091138; https://doi.org/10.3390/biom14091138 | HPO: HP:0001761 pes cavus, HP:0001159 syndactyl? not applicable; prioritize HP:0001765 hammer toe, HP:0009467 claw hand if used in KB |


*Table: This table compiles compact, citation-backed facts on Charcot-Marie-Tooth disease type 1 and CMT1A for knowledge-base use, spanning classification, epidemiology, genetics, mechanisms, outcomes, and current phase III therapeutic trials.*