Charcot-Marie-Tooth Disease

Mendelian MONDO:0015626 Show in embeddings browser Peripheral Neuropathy

Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of the peripheral nervous system, with a prevalence of roughly 1 in 2,500. CMT is genetically and pathologically heterogeneous, with over 100 causative genes identified. This is the umbrella classification entry for the CMT family; the detailed pathophysiology is curated in two mechanism-coherent compartment entries that cleave the CMT pathograph at its natural seam — the primary cellular lesion. The demyelinating / Schwann-cell compartment (Charcot-Marie-Tooth disease type 1; PMP22, MPZ, GJB1) and the axonal / neuronal compartment (Charcot-Marie-Tooth disease type 2; MFN2, RAB7A, NEFL, GARS1, SORD) each hold gene-level mechanisms that converge on a single shared terminal node — length-dependent distal axonal degeneration — which produces the uniform clinical phenotype of slowly progressive distal weakness and atrophy, sensory loss, foot deformity (pes cavus, hammer toes), and depressed deep tendon reflexes regardless of the upstream gene. Inheritance can be autosomal dominant (most CMT1, CMT2), autosomal recessive (CMT4), or X-linked (CMTX). The single most common subtype is CMT1A, a 1.4 Mb duplication of chromosome 17p11.2 containing PMP22. Hereditary neuropathy with liability to pressure palsies (HNPP), allelic to CMT1A but caused by the reciprocal PMP22 deletion, is curated separately because its terminal node differs (focal, reversible, compression-sensitive conduction block rather than dying-back degeneration). Gene-defined numbered subtypes are curated as has_subtypes rows on the compartment entry whose primary lesion they share rather than on this umbrella, so that each gene reaches the demyelinating or axonal mechanism it acts through: FBLN5 (CMT1H) and ITPR3 (CMT1J) sit on the type 1 entry, and CADM3 (CMT2FF), JAG1 (CMT2HH), SLC12A6 (CMT2II), ARHGAP19 (CMT2KK), DARS2 (CMT2LL) and COX18 (CMT2MM) on the type 2 entry, alongside the MFN2 allelic and phenotypic variants CMT2A2B and HMSN VIA.

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4
Phenotypes
1
Hypotheses
2
Gaps
4
Genes
7
Medical Actions
5
Subtypes
1
References
1
Deep Research
1
Hyp. Reports
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Subtypes

5
Charcot-Marie-Tooth Disease Type 1 (Demyelinating)
Autosomal dominant demyelinating form with reduced motor nerve conduction velocities (<38 m/s in median nerve). The most common clinical category; in a 1,515-patient specialist cohort, CMT1 comprised 41.0% of cases and achieved the highest genetic diagnosis rate (96.8%). CMT1A (PMP22 duplication) is the dominant subtype. Schwann cell dysfunction with onion-bulb formation on nerve biopsy.
Show evidence (1 reference)
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"621 patients had CMT1 (41.0%)"
Single-centre 1,515-patient specialist cohort quantifies CMT1 at 41.0% of CMT presentations.
Charcot-Marie-Tooth Disease Type 2 (Axonal)
Autosomal dominant axonal form with normal or near-normal nerve conduction velocities but reduced amplitudes. Primary axonal degeneration. Many causative genes identified including MFN2, MPZ, NEFL, GDAP1. Comprised 19.4% of cases in the Brain 2024 specialist cohort, with a substantially lower genetic diagnosis rate (<50%) than CMT1.
Show evidence (2 references)
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"294 CMT2 (19.4%)"
Specialist-cohort frequency of axonal CMT2.
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"Diagnostic rates remained less than 50% in CMT2, HMN and complex neuropathies."
Quantifies the diagnostic gap in axonal CMT relative to demyelinating CMT1.
X-Linked Charcot-Marie-Tooth Disease
X-linked inheritance, most commonly caused by mutations in GJB1 encoding connexin-32 (CMTX1). Males more severely affected than carrier females. Intermediate electrophysiology between CMT1 and CMT2. GJB1 was the second most common genetic diagnosis (13.0% of solved cases) in the Brain 2024 cohort.
Show evidence (1 reference)
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"then GJB1 (CMTX1; 151/1165, 13.0%)"
GJB1/CMTX1 is the second most common genetically resolved CMT subtype.
Charcot-Marie-Tooth Disease Type 4 (Autosomal Recessive)
Autosomal recessive forms. Generally earlier onset and more severe than autosomal dominant CMT. Includes both demyelinating and axonal pathologies depending on the gene.
Hereditary Neuropathy with Liability to Pressure Palsies
Allelic to CMT1A but caused by deletion (rather than duplication) of the same chromosome 17p11.2 region containing PMP22. PMP22 underexpression leads to recurrent, focal, pressure-induced demyelinating mononeuropathies. Comprised 4.8% of cases (and 6.2% of solved diagnoses) in the Brain 2024 cohort.
Show evidence (1 reference)
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"PMP22 deletion (HNPP; 72/1165, 6.2%)"
Frequency of PMP22-deletion-driven HNPP in the specialist cohort.
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Mechanistic Hypotheses

1
Canonical PMP22 / MPZ / Axonal & Demyelinating Peripheral Neuropathy Model
canonical_pmp22_mpz_axonal_demyelinating_neuropathy_model CANONICAL
Evidence balance 21 support
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited peripheral neuropathies caused by variants in >100 genes encoding myelin components (PMP22, MPZ, GJB1) and axonal cytoskeleton/transport proteins (MFN2, NEFL), plus other Schwann-cell-axon interface factors. KIF1B is a historical CMT2A1 candidate gene, but it carries only Limited ClinGen gene-disease validity evidence, not the established causal status of MFN2 (see notes). CMT1A (most common, PMP22 duplication on 17p11.2) produces demyelinating neuropathy through PMP22 overexpression-driven Schwann cell dysfunction and secondary axonal loss. Axonal CMT2 forms (MFN2, MPZ, others) primarily impair axonal function. The uniform clinical phenotype — distal motor and sensory loss in a length-dependent pattern, with foot deformity, distal weakness, and absent reflexes — frequently converges on length-dependent axonal degeneration as a late-stage correlate of disability across CMT1A and CMT2 subtypes, though not a universal mechanism in every model (see notes). The PMP22 duplication CMT1A mouse and rat models recapitulate the human phenotype, and PMP22-lowering ASO and PXT3003 (low-dose drug combination) corroborate the PMP22-dosage axis as a canonical mechanism in the most common subtype.
Retained as CANONICAL. The 2026 openscientist hypothesis-search report (kb/hypotheses/Charcot-Marie-Tooth_Disease/canonical_pmp22_mpz_axonal_demyelinating_neuropathy_model) finds the broad canonical framework SUPPORTED, but several report-level claims required source-, model-, subtype-, and species-scoping before independent reconciliation into this entry (issue #7405; sidecar assessment in PR #7406). Core architecture remains validated: >100 genes show genetic heterogeneity; CMT1A and CMT2 subtypes frequently converge on length-dependent axonal degeneration as a late-stage correlate of disability, though not as a universal sufficient mechanism — adult C3-PMP22 (CMT1A) model mice show no detectable myelinated-fibre loss despite functional impairment (PMID:21487305); transgenic models recapitulate the human phenotype. PMP22 duplication accounts for 505/1165 (43.3%) of genetically solved cases and 505/1515 (33.3%) of all clinically diagnosed participants in a single specialist-centre cohort (PMID:38481354, cited below via DOI:10.1093/brain/awae064); a separately cited ~60% figure (PMID:31852984) is a background statement about the share of pathogenic CMT variants attributable to the PMP22 duplication, not a comparable diagnosed-case estimate, and should not be blended with the cohort figure into a single "43-60%" range. Seven substantive, source-scoped refinements: (1) dysmyelination is a real developmental component, not a categorical replacement for demyelinating classification — dermal-fibre biopsies from 32 CMT1A patients show uniformly shortened internodal length and absent segmental demyelination, suggesting a developmental internode defect (PMID:19923170), and long-term PMP22-overexpressing mice show delayed, incomplete developmental myelination with stable adult myelin (PMID:21487305) — conventional demyelinating features and a developmental dysmyelination component coexist, they are not mutually exclusive; (2) PMP22 acting as a structural organizer of nodal/Schmidt-Lanterman-incisure architecture is shown specifically in CMT1A and HNPP model mice (PMID:41400104), not yet established as a human CMT-wide mechanism; (3) UPR/ER-stress modulation (Sephin1/IFB-088) improved neuropathy in C3-PMP22 (CMT1A) and MpzR98C (CMT1B) mice (PMID:35501630) — convergence is demonstrated across these two mouse models, not broadly across CMT subtypes or in humans; (4) SARM1 acting as an executioner of axonal degeneration, with a feedback loop to mitochondrial dysfunction, is shown in one Mfn2-H361Y CMT2A rat model (PMID:36287202) — a single-model finding, not yet a cross-subtype or human result (SARM1 inhibitors are in development); (5) macrophage/CSF1-driven secondary neuroinflammation amplifying demyelination is documented predominantly in CMT1B (P0+/- mice) and CMT1X (connexin-32-deficient mice) models (PMID:16775375 review; PMID:26865613), not established as a general driver across all CMT subtypes; systemic terminal complement (C6) inhibition in two PMP22-overexpressing CMT1A mouse models reduced neuroinflammation but did not improve motor function (PMID:36926597) — this was a mouse experiment, not a failed human trial, and must not be counted among failed human CMT1A trials; (6) cholesterol trafficking is disrupted by both loss- and gain-of-function PMP22 mutations, but the rescue evidence is directionally specific: myelination deficits in dorsal root ganglia explants were improved by cholesterol supplementation only in heterozygous PMP22-deficient (loss-of-function) mice (PMID:32511821) — this does not support a supplementation strategy for PMP22-duplication (gain-of-function) CMT1A, the reverse direction; (7) KIF1B is listed among the CMT axonal-transport genes, but the KIF1B-CMT2A1 relationship arose from a small pedigree base, and ClinGen's Charcot-Marie-Tooth Disease Gene Curation Expert Panel classified it as Limited in June 2026 (CGGV:assertion_ae6ffeae-9609-47bf-89a9-4863cf6ef05c-2026-06-12T160000.000Z, cited below) — it should not be presented as equivalent in evidentiary weight to the established MFN2-CMT2A relationship. Human proof-of-concept for PMP22-lowering therapies remains the critical translational gap: no cited study demonstrates clinical benefit in humans from direct PMP22 lowering; the five human ascorbic-acid trials to date were negative, and only PXT3003 showed a modest, single-trial Phase III benefit. Preclinical human-cell evidence is further along than the clinical evidence: PMP22 downregulation ameliorated myelin defects in patient-derived CMT1A iPSC-organoids (PMID:36511878), and AAV-mediated editing of the PMP22 duplication rescued disease features in patient-derived CMT1A iPS Schwann cells (PMID:38017287) — the PMP22-dosage axis therefore has direct human-cell (not yet human-trial) proof of concept, alongside the rodent validation. ASO and AAV9-miRNA gene therapies are advancing toward clinical translation. A 2026-09 reconciliation pass against the same openscientist report added source-scoped citations for three claims this entry previously asserted without one, plus two qualifications it did not carry at all. (a) The failed human arm is now cited: five ascorbic-acid trials were undertaken worldwide and none demonstrated significant effectiveness (PMID:26450076), the largest being a 2-year randomised trial in 277 CMT1A adults that found no CMTNS difference from placebo at 24 months (PMID:21393063). Saturable ascorbate absorption has been proposed as the reason they failed (PMID:23525455), but that paper argues the case pharmacokinetically rather than testing it against the alternatives (target biology, intraneural exposure, outcome sensitivity, model fidelity), so it is deliberately not curated here as an established cause. (b) Direct PMP22 lowering is now cited at the treatment level: post-onset antisense oligonucleotide treatment restored myelination and nerve conduction in two rodent CMT1A models (PMID:29202483), and an intrathecal AAV9 vector carrying the artificial miRNA miR871 lowered PMP22 and improved disease in a humanized mouse model, with dosing, toxicity and biodistribution work in mice and non-human primates (PMID:41948127). Both remain preclinical, so the human-validation gap above is unchanged. (c) Two further qualifications of the convergence framing: Schwann cells mount an endogenous c-Jun repair programme that prevents loss of distal myelinated sensory axons in the C3-PMP22 CMT1A model (PMID:25216747), so axonal degeneration is actively opposed rather than following inevitably from the myelin lesion; and children with CMT2A progress measurably faster on the CMTPedS than children with CMT1A over two years (PMID:28796392), so a shared terminal node does not imply a shared disease course. Lipidomic and transcriptomic profiling of CMT1A mouse sciatic nerve and of patient-derived iPSC Schwann cell precursors extends the cholesterol branch into the duplication (gain-of-function) direction and into human cells (PMID:38743588), which the PMP22-deficient explant rescue in refinement (6) does not cover. Plasma NfL and GFAP are curated below as severity-correlated biomarkers; no CMT biomarker has been shown to change in response to an effective disease-modifying therapy, which is recorded as a knowledge gap rather than as biomarker validation.
Deep research
OpenScientist citations 42 citations 2026-05-25T14:47:10.689285
Show evidence (21 references)
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%)"
Existing canonical mechanism citation in the dismech knowledge base, used as the seed for the hypothesis-search deep-research run.
PMID:31852984 SUPPORT Human Clinical
"the recurrent PMP22 duplication accounting for about 60% of pathogenic variations"
Background statement about the share of pathogenic CMT variants attributable to PMP22 duplication (not a diagnosed-case cohort estimate). Graded PARTIAL because this figure is not directly comparable to the 43.3%/33.3% diagnosed-case denominators from PMID:38481354 and should not be blended with them into a single range (issue #7405).
PMID:19923170 SUPPORT Human Clinical
"Internodal length was uniformly shortened in patients with Charcot-Marie-Tooth disease type 1A, compared with those in normal controls (P < 0.0001). Segmental demyelination was absent in the Charcot-Marie-Tooth disease type 1A group, but identifiable in all patients with chronic inflammatory..."
Dermal-fibre biopsies from 32 CMT1A patients support a developmental internode defect alongside, not instead of, conventional demyelinating classification.
+ 18 more references
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Discussions and Knowledge Gaps

2
Does lowering PMP22 modify disease in people with CMT1A, as it does in rodent models?
KNOWLEDGE GAP OPEN human_proof_of_concept_pmp22_lowering
Attached to
mechanistic_hypotheses#canonical_pmp22_mpz_axonal_demyelinating_neuropathy_model treatments#PMP22-Lowering Antisense Oligonucleotide treatments#AAV9-miR871 PMP22 Silencing Gene Therapy
The PMP22 dosage axis is the load-bearing claim of the canonical model and is validated only in rodents and in patient-derived cells. Antisense oligonucleotide and AAV9-miRNA approaches both improve established disease in rodent CMT1A models, and PMP22 downregulation rescues myelin defects in patient-derived organoids and iPS Schwann cells, but no human trial of direct PMP22 lowering has reported results. Every agent actually given to people with CMT1A has acted indirectly: five ascorbic-acid trials were negative, and PXT3003 is a three-drug combination whose modest phase III benefit cannot be attributed to PMP22 lowering specifically. Until a first-in-human trial of direct lowering reads out, the axis is a preclinical inference rather than a demonstrated human mechanism.
Proposed experiments
First-in-human dose-escalation trial of direct PMP22 lowering in CMT1A
exp_cmt_first_in_human_pmp22_lowering
Phase 1/2 dose escalation in adults with genetically confirmed CMT1A of mild to moderate severity, using either a PMP22 antisense oligonucleotide or an intrathecal AAV9-miRNA vector. Pair target engagement, measured as PMP22 mRNA in serial skin biopsies, with the two outcome measures that have shown movement over 12 months in this disease: quantitative calf muscle MRI fat fraction and plasma neurofilament light chain.
Decision criterion
Dose-dependent reduction of skin PMP22 mRNA accompanied by stabilisation of calf muscle fat fraction and of plasma NfL against the untreated natural-history trajectory would establish PMP22 dosage as a modifiable human mechanism.
Would support
mechanistic_hypotheses#canonical_pmp22_mpz_axonal_demyelinating_neuropathy_model
Would refute
mechanistic_hypotheses#canonical_pmp22_mpz_axonal_demyelinating_neuropathy_model
Supporting outcome
  • Skin PMP22 mRNA falls dose-dependently, and calf muscle fat fraction and plasma NfL stabilise relative to the natural-history trajectory.
Refuting outcome
  • Skin PMP22 mRNA falls to the degree that rescues rodent models while calf muscle fat fraction and plasma NfL continue on their untreated trajectory, indicating that PMP22 dosage is not rate-limiting for established human disease.
Show evidence (1 reference)
PMID:41948127 SUPPORT Model Organism
"To support clinical translation, we confirmed on-target specificity of miR871 for PMP22 in vitro, identified a safe and effective dosing range in mice, demonstrated absence of significant toxicity in rodents and non-human primates (NHPs), and performed a detailed AAV biodistribution study in a..."
The most advanced direct-lowering programme describes its own package as work done to support clinical translation, which is a statement that the human step has not yet been taken.
Has any CMT biomarker been shown to change in response to an effective disease-modifying therapy?
KNOWLEDGE GAP OPEN cmt_biomarker_response_to_therapy
Attached to
biochemical#Plasma Neurofilament Light Chain biochemical#Plasma Glial Fibrillary Acidic Protein
Quantitative calf muscle MRI fat fraction, plasma NfL, and plasma GFAP all separate CMT from controls and track severity, and fat fraction moves enough over 12 months to be proposed as a trial endpoint. None has been measured against a therapy that works, because until PXT3003 no CMT therapy did, and PXT3003 was not run with these readouts. Responsiveness to untreated progression is necessary but not sufficient for surrogacy: a marker can track decline faithfully and still fail to move when the upstream mechanism is corrected. Treating any of these as a validated surrogate endpoint would overstate what has been shown, and the biomarker substudy belongs inside the first direct-lowering trial rather than after it.
Show evidence (1 reference)
PMID:39957630 SUPPORT Human Clinical
"We demonstrated a consistent progression of calf muscle MRI fat over 4 years, significant longitudinal correlation between CMT Examination Score and calf muscle fat, and potential as a bridging biomarker by 1 year change in fat correlating with long-term clinical progression."
The strongest responsiveness result available for any CMT biomarker, from 20 untreated CMT1A patients followed for a mean of four years. The authors claim potential as a bridging biomarker rather than demonstrated surrogacy, which is the boundary this gap records.
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Phenotypes

4
Limbs 1
Pes Cavus HP:0001761 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pes cavus (HP:0001761). HP:0001761 is a phenotype from the Human Phenotype Ontology.
Musculoskeletal 1
Distal Muscle Weakness HP:0002460 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal muscle weakness (HP:0002460), qualified as course progressive. HP:0002460 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Nervous System 2
Decreased Tendon Reflexes Hyporeflexia HP:0001265 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hyporeflexia (HP:0001265). HP:0001265 is a phenotype from the Human Phenotype Ontology.
Distal Sensory Loss Distal sensory impairment HP:0002936 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Distal sensory impairment (HP:0002936). HP:0002936 is a phenotype from the Human Phenotype Ontology.
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Genetic Associations

4
PMP22 (Causal)
Gene: PMP22 hgnc:9118 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is PMP22 (hgnc:9118). hgnc:9118 is a gene from the HUGO Gene Nomenclature Committee.
Show evidence (1 reference)
DOI:10.1093/brain/awae064 SUPPORT Human Clinical
"The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%), then GJB1 (CMTX1; 151/1165, 13.0%), PMP22 deletion (HNPP; 72/1165, 6.2%) and MFN2 (CMT2A; 46/1165, 3.9%)"
PMP22 duplication (43.3%) and deletion (6.2%) together drive nearly half of all genetically resolved CMT.
GJB1 (Causal)
Gene: GJB1 hgnc:4283 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is GJB1 (hgnc:4283). hgnc:4283 is a gene from the HUGO Gene Nomenclature Committee.
MFN2 (Causal)
Gene: MFN2 hgnc:16877 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MFN2 (hgnc:16877). hgnc:16877 is a gene from the HUGO Gene Nomenclature Committee.
MPZ (Causal)
Gene: MPZ hgnc:7225 gene page HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is MPZ (hgnc:7225). hgnc:7225 is a gene from the HUGO Gene Nomenclature Committee.
💊

Medical Actions

7
Physical and Occupational Therapy
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Platform: Behavioral / lifestyle
Mainstay of supportive care to maintain mobility and function.
Orthotic Bracing
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Ankle-foot orthoses to compensate for foot drop and improve gait.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counseling for affected individuals and families.
PXT3003
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: baclofen CHEBI:2972 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses baclofen (CHEBI:2972). CHEBI:2972 is a therapeutic agent from Chemical Entities of Biological Interest. naltrexone CHEBI:7465 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses naltrexone (CHEBI:7465). CHEBI:7465 is a therapeutic agent from Chemical Entities of Biological Interest.
Oral fixed-dose combination of low-dose baclofen, naltrexone, and sorbitol designed to lower PMP22 expression and improve axonal function in CMT1A. Phase III trials (PLEO-CMT NCT02579759 completed, PREMIER NCT04762758).
Show evidence (3 references)
DOI:10.3390/genes14071391 SUPPORT Other
"Compounds such as PXT3003, which are being clinically and preclinically investigated, and a broad array of therapeutic agents and their corresponding mechanisms are discussed."
Establishes PXT3003 as an active clinical/preclinical therapeutic candidate for CMT.
PMID:34656144 SUPPORT Human Clinical
"The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile."
PLEO-CMT phase III result in 323 adults with mild-to-moderate CMT1A. The high-dose arm beat placebo on the Overall Neuropathy Limitations Scale (mean difference 0.37 points, p = 0.008). This is the only positive pharmacological trial in CMT1A to date and the effect size is small.
PMID:34656144 SUPPORT Human Clinical
"The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group."
Records the conduct problem that qualifies the result above: the arm that produced the positive finding was stopped early for formulation crystallization, and the statistical analysis plan was adapted before database lock to handle the resulting missing data. The trial supports PXT3003 as promising, not as established disease-modifying therapy.
AAV9-MFN2 Gene Therapy
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
Intrathecal delivery of an AAV9 vector expressing MFN2 to restore ER-mitochondria contacts and prevent axonal degeneration in CMT2A. In vivo studies demonstrate therapeutic efficacy even when administered after symptom onset, with good tolerability profile.
Show evidence (1 reference)
PMID:42301793 SUPPORT Model Organism
"Intrathecal delivery of an AAV9 vector expressing MFN2WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function"
Demonstrates that AAV9-MFN2 gene therapy restores ER-mitochondria contact homeostasis and prevents axonal degeneration in transgenic CMT2A models and patient-derived motor neurons.
PMP22-Lowering Antisense Oligonucleotide
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Platform: Antisense oligonucleotide RNase H knockdown Chemistry: Constrained ethyl (cEt)
RNA target: PMP22 hgnc:9118 HUGO Gene Nomenclature Committee (hgnc) Relation: this treatment base-pairs with the transcript of this gene This treatment base-pairs with the transcript of PMP22 (hgnc:9118). hgnc:9118 is a gene from the HUGO Gene Nomenclature Committee. PMP22 mRNA
Investigational antisense oligonucleotides that suppress PMP22 mRNA in affected peripheral nerve, addressing the causal gene-dosage lesion of CMT1A rather than a downstream consequence of it. The published rodent proof of concept used 16-mer chimeric gapmer phosphorothioate oligonucleotides carrying constrained-ethyl residues at positions 1 to 3 and 14 to 16, acting through RNase H-mediated degradation of the target transcript. Preclinical only: no human trial of direct PMP22 lowering has reported results, which is this entry's central translational gap.
Show evidence (2 references)
PMID:29202483 SUPPORT Model Organism
"Notably, initiation of ASO treatment after disease onset restored myelination, MNCV, and CMAP almost to levels seen in WT animals."
Post-onset dosing reversed myelination and nerve-conduction deficits in two rodent CMT1A models. Because treatment started after disease was established, this is the strongest preclinical argument that the PMP22 dosage lesion drives an ongoing, reversible process rather than only a fixed developmental one. Rodent models only.
PMID:29202483 SUPPORT Model Organism
"Furthermore, we demonstrated that reduction of PMP22 mRNA in skin biopsies from ASO-treated rats is a suitable biomarker for evaluating target engagement in response to ASO therapy."
Establishes skin-biopsy PMP22 mRNA as the target-engagement readout proposed for a first-in-human PMP22-lowering trial, which is the measure the discriminating test in the knowledge gap below depends on.
AAV9-miR871 PMP22 Silencing Gene Therapy
Action: gene therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is gene therapy (NCIT:C15238). NCIT:C15238 is a clinical intervention from the NCI Thesaurus. Ontology label: Gene Therapy NCIT:C15238
Platform: Gene therapy
Lumbar intrathecal AAV9 delivering a U6-driven artificial microRNA (miR871) that silences PMP22 mRNA in Schwann cells, developed as a one-time treatment for CMT1A. Preclinical: efficacy in a humanized CMT1A mouse model, with dose ranging, toxicity, and vector biodistribution work in mice and non-human primates assembled to support a first-in-human trial.
Show evidence (2 references)
PMID:41948127 SUPPORT Model Organism
"A single injection produced long-term miR871 expression, triggered selective RNA interference against the PMP22 mRNA, and subsequently lowered protein levels and improved disease manifestations in a humanized CMT1A model."
Single-dose intrathecal AAV9 achieved sustained, selective PMP22 knockdown and phenotypic improvement in a humanized CMT1A mouse, independently corroborating the ASO result that lowering PMP22 modifies established disease in rodents.
PMID:41948127 SUPPORT Model Organism
"We found vector biodistribution and miR871 expression in distal peripheral nerves, PMP22 target engagement in mice and NHPs, and silencing to levels expected to support normal myelination in humans."
Reaching distal peripheral nerve is the delivery problem specific to a length-dependent neuropathy, and target engagement was shown in non-human primates as well as mice. The human silencing level is extrapolated, not measured, so this supports translational readiness and not human efficacy.
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Biochemical Markers

2
Plasma Neurofilament Light Chain (Elevated relative to controls)
Context: Genetically confirmed CMT of mixed subtype versus matched controls, measured in plasma by single-molecule array.
Show evidence (1 reference)
PMID:39882365 SUPPORT Human Clinical
"NfL and GFAP levels were correlated with the CMTNSv2 score (rs = 0.46, p = 0.002; rs = 0.31, p = 0.04)."
In 44 genetically confirmed CMT patients and 44 matched controls, plasma NfL correlated with the CMT Neuropathy Score version 2. The correlation is moderate and cross-sectional, so it supports NfL as a severity indicator rather than as a progression or treatment-response measure.
Plasma Glial Fibrillary Acidic Protein (Elevated relative to controls)
Context: Genetically confirmed CMT of mixed subtype versus matched controls, measured in plasma by single-molecule array.
Show evidence (1 reference)
PMID:39882365 SUPPORT Human Clinical
"In the group of patients with CMT, the concentrations of GDF15, FGF21, NfL, and GFAP were significantly higher than in the control group (p < 0.05)."
Establishes that plasma GFAP is raised in CMT relative to controls in this 44-case, 44-control study. The study does not localise the glial signal, so the elevation is curated as an observed association only.
📊

Prevalence

1
Auckland region, New Zealand (population-based multi-source ascertainment)
Point Prevalence 15.7 per 100,000 (11.6–21.0) 1–9 per 10,000
Age-standardised point prevalence from a population-based study using multiple case ascertainment sources (primary care, hospitals, neuromuscular disease registry, community organisations, self-referral) in the Auckland Region of New Zealand, 2016. Highest prevalence was in the 50–64 age group (25.2/100,000). Estimates from single ascertainment sources may underestimate true prevalence. The commonly cited "1 in 2,500" figure (40/100,000) likely reflects earlier clinical-series estimates and may include broader ascertainment; the NZ population-based rate is lower.
Show evidence (1 reference)
PMID:31203252 SUPPORT Human Clinical
"Age-standardised point prevalence of all CMT cases was 15.7 per 100 000"
Population-based study using multiple ascertainment sources in the Auckland Region of New Zealand reports an age-standardised point prevalence of 15.7 per 100,000 (95% CI 11.6–21.0) for all CMT.
{ }

Source YAML

click to show 
name: Charcot-Marie-Tooth Disease
creation_date: "2026-05-12T20:30:00Z"
category: Mendelian
disease_term:
  preferred_term: Charcot-Marie-Tooth disease
  term:
    id: MONDO:0015626
    label: Charcot-Marie-Tooth disease
parents:
- Peripheral Neuropathy
description: >-
  Charcot-Marie-Tooth disease (CMT) is the most common inherited disorder of
  the peripheral nervous system, with a prevalence of roughly 1 in 2,500.
  CMT is genetically and pathologically heterogeneous, with over 100 causative
  genes identified. This is the umbrella classification entry for the CMT family;
  the detailed pathophysiology is curated in two mechanism-coherent compartment
  entries that cleave the CMT pathograph at its natural seam — the primary
  cellular lesion. The demyelinating / Schwann-cell compartment (Charcot-Marie-Tooth
  disease type 1; PMP22, MPZ, GJB1) and the axonal / neuronal compartment
  (Charcot-Marie-Tooth disease type 2; MFN2, RAB7A, NEFL, GARS1, SORD) each hold
  gene-level mechanisms that converge on a single shared terminal node —
  length-dependent distal axonal degeneration — which produces the uniform
  clinical phenotype of slowly progressive distal weakness and atrophy, sensory
  loss, foot deformity (pes cavus, hammer toes), and depressed deep tendon
  reflexes regardless of the upstream gene. Inheritance can be autosomal dominant
  (most CMT1, CMT2), autosomal recessive (CMT4), or X-linked (CMTX). The single
  most common subtype is CMT1A, a 1.4 Mb duplication of chromosome 17p11.2
  containing PMP22. Hereditary neuropathy with liability to pressure palsies
  (HNPP), allelic to CMT1A but caused by the reciprocal PMP22 deletion, is curated
  separately because its terminal node differs (focal, reversible,
  compression-sensitive conduction block rather than dying-back degeneration).
  Gene-defined numbered subtypes are curated as has_subtypes rows on the
  compartment entry whose primary lesion they share rather than on this umbrella,
  so that each gene reaches the demyelinating or axonal mechanism it acts through:
  FBLN5 (CMT1H) and ITPR3 (CMT1J) sit on the type 1 entry, and CADM3 (CMT2FF),
  JAG1 (CMT2HH), SLC12A6 (CMT2II), ARHGAP19 (CMT2KK), DARS2 (CMT2LL) and COX18
  (CMT2MM) on the type 2 entry, alongside the MFN2 allelic and phenotypic variants
  CMT2A2B and HMSN VIA.
has_subtypes:
- name: CMT1
  display_name: Charcot-Marie-Tooth Disease Type 1 (Demyelinating)
  description: >-
    Autosomal dominant demyelinating form with reduced motor nerve conduction
    velocities (<38 m/s in median nerve). The most common clinical category;
    in a 1,515-patient specialist cohort, CMT1 comprised 41.0% of cases and
    achieved the highest genetic diagnosis rate (96.8%). CMT1A (PMP22
    duplication) is the dominant subtype. Schwann cell dysfunction with
    onion-bulb formation on nerve biopsy.
  evidence:
  - reference: DOI:10.1093/brain/awae064
    reference_title: "Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "621 patients had CMT1 (41.0%)"
    explanation: Single-centre 1,515-patient specialist cohort quantifies CMT1 at 41.0% of CMT presentations.
- name: CMT2
  display_name: Charcot-Marie-Tooth Disease Type 2 (Axonal)
  description: >-
    Autosomal dominant axonal form with normal or near-normal nerve conduction
    velocities but reduced amplitudes. Primary axonal degeneration. Many
    causative genes identified including MFN2, MPZ, NEFL, GDAP1. Comprised
    19.4% of cases in the Brain 2024 specialist cohort, with a substantially
    lower genetic diagnosis rate (<50%) than CMT1.
  evidence:
  - reference: DOI:10.1093/brain/awae064
    reference_title: "Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "294 CMT2 (19.4%)"
    explanation: Specialist-cohort frequency of axonal CMT2.
  - reference: DOI:10.1093/brain/awae064
    reference_title: "Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Diagnostic rates remained less than 50% in CMT2, HMN and complex neuropathies."
    explanation: Quantifies the diagnostic gap in axonal CMT relative to demyelinating CMT1.
- name: CMTX
  display_name: X-Linked Charcot-Marie-Tooth Disease
  description: >-
    X-linked inheritance, most commonly caused by mutations in GJB1 encoding
    connexin-32 (CMTX1). Males more severely affected than carrier females.
    Intermediate electrophysiology between CMT1 and CMT2. GJB1 was the
    second most common genetic diagnosis (13.0% of solved cases) in the
    Brain 2024 cohort.
  evidence:
  - reference: DOI:10.1093/brain/awae064
    reference_title: "Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "then GJB1 (CMTX1; 151/1165, 13.0%)"
    explanation: GJB1/CMTX1 is the second most common genetically resolved CMT subtype.
- name: CMT4
  display_name: Charcot-Marie-Tooth Disease Type 4 (Autosomal Recessive)
  description: >-
    Autosomal recessive forms. Generally earlier onset and more severe than
    autosomal dominant CMT. Includes both demyelinating and axonal pathologies
    depending on the gene.
- name: HNPP
  display_name: Hereditary Neuropathy with Liability to Pressure Palsies
  description: >-
    Allelic to CMT1A but caused by deletion (rather than duplication) of the
    same chromosome 17p11.2 region containing PMP22. PMP22 underexpression
    leads to recurrent, focal, pressure-induced demyelinating mononeuropathies.
    Comprised 4.8% of cases (and 6.2% of solved diagnoses) in the Brain 2024
    cohort.
  evidence:
  - reference: DOI:10.1093/brain/awae064
    reference_title: "Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PMP22 deletion (HNPP; 72/1165, 6.2%)"
    explanation: Frequency of PMP22-deletion-driven HNPP in the specialist cohort.
mechanistic_hypotheses:
- hypothesis_group_id: canonical_pmp22_mpz_axonal_demyelinating_neuropathy_model
  hypothesis_label: Canonical PMP22 / MPZ / Axonal & Demyelinating Peripheral Neuropathy Model
  status: CANONICAL
  description: >-
    Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of inherited
    peripheral neuropathies caused by variants in >100 genes encoding myelin components (PMP22, MPZ,
    GJB1) and axonal cytoskeleton/transport proteins (MFN2, NEFL), plus other Schwann-cell-axon
    interface factors. KIF1B is a historical CMT2A1 candidate gene, but it carries only Limited ClinGen
    gene-disease validity evidence, not the established causal status of MFN2 (see notes). CMT1A (most
    common, PMP22 duplication on 17p11.2) produces demyelinating neuropathy through PMP22
    overexpression-driven Schwann cell dysfunction and secondary axonal loss. Axonal CMT2 forms (MFN2,
    MPZ, others) primarily impair axonal function. The uniform clinical phenotype — distal motor and
    sensory loss in a length-dependent pattern, with foot deformity, distal weakness, and absent
    reflexes — frequently converges on length-dependent axonal degeneration as a late-stage correlate of
    disability across CMT1A and CMT2 subtypes, though not a universal mechanism in every model (see
    notes). The PMP22 duplication CMT1A mouse and rat models recapitulate the human phenotype, and
    PMP22-lowering ASO and PXT3003 (low-dose drug combination) corroborate the PMP22-dosage axis as a
    canonical mechanism in the most common subtype.
  notes: >-
    Retained as CANONICAL. The 2026 openscientist hypothesis-search
    report
    (kb/hypotheses/Charcot-Marie-Tooth_Disease/canonical_pmp22_mpz_axonal_demyelinating_neuropathy_model)
    finds the broad canonical framework SUPPORTED, but several
    report-level claims required source-, model-, subtype-, and
    species-scoping before independent reconciliation into this
    entry (issue #7405; sidecar assessment in PR #7406). Core
    architecture remains validated: >100 genes show genetic
    heterogeneity; CMT1A and CMT2 subtypes frequently converge on
    length-dependent axonal degeneration as a late-stage correlate of
    disability, though not as a universal sufficient mechanism —
    adult C3-PMP22 (CMT1A) model mice show no detectable
    myelinated-fibre loss despite functional impairment (PMID:21487305);
    transgenic models recapitulate the human phenotype. PMP22
    duplication accounts for
    505/1165 (43.3%) of genetically solved cases and 505/1515
    (33.3%) of all clinically diagnosed participants in a single
    specialist-centre cohort (PMID:38481354, cited below via
    DOI:10.1093/brain/awae064); a separately cited ~60% figure
    (PMID:31852984) is a background statement about the share of
    pathogenic CMT variants attributable to the PMP22 duplication,
    not a comparable diagnosed-case estimate, and should not be
    blended with the cohort figure into a single "43-60%" range. Seven
    substantive, source-scoped refinements: (1) dysmyelination is a
    real developmental component, not a categorical replacement for
    demyelinating classification — dermal-fibre biopsies from 32
    CMT1A patients show uniformly shortened internodal length and
    absent segmental demyelination, suggesting a developmental
    internode defect (PMID:19923170), and long-term
    PMP22-overexpressing mice show delayed, incomplete developmental
    myelination with stable adult myelin (PMID:21487305) —
    conventional demyelinating features and a developmental
    dysmyelination component coexist, they are not mutually
    exclusive; (2) PMP22 acting as a structural organizer of
    nodal/Schmidt-Lanterman-incisure architecture is shown
    specifically in CMT1A and HNPP model mice (PMID:41400104), not
    yet established as a human CMT-wide mechanism; (3) UPR/ER-stress
    modulation (Sephin1/IFB-088) improved neuropathy in C3-PMP22
    (CMT1A) and MpzR98C (CMT1B) mice (PMID:35501630) — convergence
    is demonstrated across these two mouse models, not broadly
    across CMT subtypes or in humans; (4) SARM1 acting as an
    executioner of axonal degeneration, with a feedback loop to
    mitochondrial dysfunction, is shown in one Mfn2-H361Y CMT2A rat
    model (PMID:36287202) — a single-model finding, not yet a
    cross-subtype or human result (SARM1 inhibitors are in
    development); (5) macrophage/CSF1-driven secondary
    neuroinflammation amplifying demyelination is documented
    predominantly in CMT1B (P0+/- mice) and CMT1X
    (connexin-32-deficient mice) models (PMID:16775375 review;
    PMID:26865613),
    not established as a general driver across all CMT subtypes;
    systemic terminal complement (C6) inhibition in two
    PMP22-overexpressing CMT1A mouse models reduced neuroinflammation
    but did not improve motor function (PMID:36926597) — this was a
    mouse experiment, not a failed human trial, and must not be
    counted among failed human CMT1A trials; (6) cholesterol
    trafficking is disrupted by both loss- and gain-of-function PMP22
    mutations, but the rescue evidence is directionally specific:
    myelination deficits in dorsal root ganglia explants were
    improved by cholesterol supplementation only in heterozygous
    PMP22-deficient (loss-of-function) mice (PMID:32511821) — this
    does not support a supplementation strategy for
    PMP22-duplication (gain-of-function) CMT1A, the reverse
    direction; (7) KIF1B is listed among the CMT axonal-transport
    genes, but the KIF1B-CMT2A1 relationship arose from a small
    pedigree base, and ClinGen's Charcot-Marie-Tooth Disease Gene
    Curation Expert Panel classified it as Limited in June 2026
    (CGGV:assertion_ae6ffeae-9609-47bf-89a9-4863cf6ef05c-2026-06-12T160000.000Z,
    cited below) — it should not be presented as equivalent in
    evidentiary weight to the established MFN2-CMT2A relationship.
    Human proof-of-concept for PMP22-lowering therapies
    remains the critical translational gap: no cited study
    demonstrates clinical benefit in humans from direct PMP22
    lowering; the five human ascorbic-acid trials to date were
    negative, and only PXT3003 showed a modest, single-trial Phase
    III benefit. Preclinical human-cell
    evidence is further along than the clinical evidence: PMP22
    downregulation ameliorated myelin defects in patient-derived
    CMT1A iPSC-organoids (PMID:36511878), and AAV-mediated editing of
    the PMP22 duplication rescued disease features in patient-derived
    CMT1A iPS Schwann cells (PMID:38017287) — the PMP22-dosage axis
    therefore has direct human-cell (not yet human-trial) proof of
    concept, alongside the rodent validation. ASO and AAV9-miRNA gene
    therapies are advancing toward clinical translation. A 2026-09
    reconciliation pass against the same openscientist report added
    source-scoped citations for three claims this entry previously asserted
    without one, plus two qualifications it did not carry at all. (a) The
    failed human arm is now cited: five ascorbic-acid trials were undertaken
    worldwide and none demonstrated significant effectiveness (PMID:26450076),
    the largest being a 2-year randomised trial in 277 CMT1A adults that found
    no CMTNS difference from placebo at 24 months (PMID:21393063). Saturable
    ascorbate absorption has been proposed as the reason they failed
    (PMID:23525455), but that paper argues the case pharmacokinetically rather
    than testing it against the alternatives (target biology, intraneural
    exposure, outcome sensitivity, model fidelity), so it is deliberately not
    curated here as an established cause. (b) Direct PMP22 lowering is now
    cited at the treatment level: post-onset antisense oligonucleotide
    treatment restored myelination and nerve conduction in two rodent CMT1A
    models (PMID:29202483), and an intrathecal AAV9 vector carrying the
    artificial miRNA miR871 lowered PMP22 and improved disease in a humanized
    mouse model, with dosing, toxicity and biodistribution work in mice and
    non-human primates (PMID:41948127). Both remain preclinical, so the
    human-validation gap above is unchanged. (c) Two further qualifications of
    the convergence framing: Schwann cells mount an endogenous c-Jun repair
    programme that prevents loss of distal myelinated sensory axons in the
    C3-PMP22 CMT1A model (PMID:25216747), so axonal degeneration is actively
    opposed rather than following inevitably from the myelin lesion; and
    children with CMT2A progress measurably faster on the CMTPedS than
    children with CMT1A over two years (PMID:28796392), so a shared terminal
    node does not imply a shared disease course. Lipidomic and transcriptomic
    profiling of CMT1A mouse sciatic nerve and of patient-derived iPSC Schwann
    cell precursors extends the cholesterol branch into the duplication
    (gain-of-function) direction and into human cells (PMID:38743588), which
    the PMP22-deficient explant rescue in refinement (6) does not cover.
    Plasma NfL and GFAP are curated below as severity-correlated biomarkers;
    no CMT biomarker has been shown to change in response to an effective
    disease-modifying therapy, which is recorded as a knowledge gap rather
    than as biomarker validation.
  evidence:
  - reference: DOI:10.1093/brain/awae064
    reference_title: "Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%)"
    explanation: >
      Existing canonical mechanism citation in the dismech
      knowledge base, used as the seed for the hypothesis-search
      deep-research run.
  - reference: PMID:31852984
    reference_title: "Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the recurrent PMP22 duplication accounting for about 60% of pathogenic variations"
    explanation: >
      Background statement about the share of pathogenic CMT
      variants attributable to PMP22 duplication (not a
      diagnosed-case cohort estimate). Graded PARTIAL because this
      figure is not directly comparable to the 43.3%/33.3%
      diagnosed-case denominators from PMID:38481354 and should not
      be blended with them into a single range (issue #7405).
  - reference: PMID:19923170
    reference_title: "Shortened internodal length of dermal myelinated nerve fibres in Charcot-Marie-Tooth disease type 1A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Internodal length was uniformly shortened in patients with Charcot-Marie-Tooth disease type 1A, compared with those in normal controls (P < 0.0001). Segmental demyelination was absent in the Charcot-Marie-Tooth disease type 1A group, but identifiable in all patients with chronic inflammatory demyelinating polyradiculoneuropathy."
    explanation: >
      Dermal-fibre biopsies from 32 CMT1A patients support a
      developmental internode defect alongside, not instead of,
      conventional demyelinating classification.
  - reference: PMID:21487305
    reference_title: "Myelin and axon pathology in a long-term study of PMP22-overexpressing mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Myelination was delayed, and normal myelination was not reached in either model but the degree of dysmyelination in C3-PMP mice was considerably less than that in C22 mice; myelination was stable in the adult mice."
    explanation: >
      Long-term PMP22-overexpressing mouse models show delayed,
      incomplete developmental myelination with stable adult myelin,
      supporting a developmental dysmyelination component.
  - reference: PMID:21487305
    reference_title: "Myelin and axon pathology in a long-term study of PMP22-overexpressing mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "In adult C3-PMP and wild-type mice, there was no detectable loss of myelinated fibers,whereas there was clear loss of myelinated fibers in C22 mice."
    explanation: >
      In the same long-term study, adult C3-PMP22 mice (the model
      the paper concludes is most representative of typical CMT1A)
      show no detectable axonal (myelinated-fibre) loss despite
      functional impairment, so length-dependent axonal degeneration
      is not a universal feature of every CMT1A model. Graded PARTIAL
      because it qualifies rather than supports the
      universal-convergence framing.
  - reference: PMID:41400104
    reference_title: "Aberrant Molecular Myelin Architecture in Charcot-Marie-Tooth Disease Type 1A and Hereditary Neuropathy With Liability to Pressure Palsies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "high-resolution confocal imaging of teased peripheral nerve fibers from CMT1A and HNPP model mice, we identified widespread disorganization of adherens junctions, mislocalization of Connexin29 and aberrant distribution of nodal ion channels"
    explanation: >
      PMP22 as a structural organizer of
      nodal/Schmidt-Lanterman-incisure myelin architecture is shown
      specifically in CMT1A and HNPP model mice, not yet as a human
      CMT-wide mechanism.
  - reference: PMID:35501630
    reference_title: "Treatment with IFB-088 Improves Neuropathy in CMT1A and CMT1B Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Both MpzR98C/ + and C3-PMP22 mice improved in motor function and neurophysiology."
    explanation: >
      UPR/ER-stress modulation (Sephin1/IFB-088) improved neuropathy
      specifically in C3-PMP22 (CMT1A) and MpzR98C (CMT1B) mice —
      convergence shown across these two mouse models, not broadly
      across CMT subtypes or in humans.
  - reference: PMID:36287202
    reference_title: "A SARM1-mitochondrial feedback loop drives neuropathogenesis in a Charcot-Marie-Tooth disease type 2A rat model."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We tested the role of SARM1 in a rat model carrying a dominant CMT2A mutation (Mfn2H361Y) that exhibits progressive dying-back axonal degeneration"
    explanation: >
      SARM1 as an executioner of axonal degeneration with a
      mitochondrial feedback loop is a single-model (one Mfn2-H361Y
      CMT2A rat) finding, not yet a cross-subtype or human result.
  - reference: PMID:16775375
    reference_title: "Role of immune cells in animal models for inherited peripheral neuropathies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "By cross-breeding P0+/- and gap-junction protein connexin 32-/- mice with immunodeficient recombination activating gene-1-deficient mutants, a substantial alleviation of the demyelinating phenotype was observed."
    explanation: >
      Direct support for immune-mediated amplification of
      demyelination specifically in P0+/- (CMT1B) and connexin-32-/-
      (CMT1X) mouse models via genetic RAG1-deficiency crosses.
  - reference: PMID:16775375
    reference_title: "Role of immune cells in animal models for inherited peripheral neuropathies."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Recently, this has also been observed in mice mildly overexpressing human peripheral myelin protein 22 kD mimicking the most common form of CMT, CMT type 1A."
    explanation: >
      CMT1A immune-cell involvement is described in this review as a
      secondary, more-recent observation, not backed by the same
      RAG1-cross causal evidence as the CMT1B/CMT1X models. Graded
      PARTIAL because it supports only an extension of the finding to
      CMT1A, not the predominant causal evidence base.
  - reference: PMID:26865613
    reference_title: "Cell-Surface and Secreted Isoforms of CSF-1 Exert Opposing Roles in Macrophage-Mediated Neural Damage in Cx32-Deficient Mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "connexin32-deficient (Cx32def) mice, a mouse model of CMT1X"
    explanation: >
      Macrophage/CSF-1-mediated neural damage is characterized
      specifically in a CMT1X (connexin-32-deficient) mouse model.
  - reference: PMID:36926597
    reference_title: "The systemic inhibition of the terminal complement system reduces neuroinflammation but does not improve motor function in mouse models of CMT1A with overexpressed PMP22."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "we inhibited systemic complement C6 in two transgenic mouse models for CMT1A, the C3-PMP22 and C3-PMP22 c-JunP0Cre models."
    explanation: >
      Terminal complement (C6) inhibition reduced neuroinflammation
      but did not improve motor function in two PMP22-overexpressing
      CMT1A mouse models — this was a mouse experiment, not a failed
      human trial (corrects a species error flagged in issue #7405).
  - reference: PMID:32511821
    reference_title: "Subcellular diversion of cholesterol by gain- and loss-of-function mutations in PMP22."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "myelination deficits in dorsal root ganglia explants from heterozygous PMP22-deficient mice were improved by cholesterol supplementation."
    explanation: >
      Cholesterol-supplementation rescue was shown specifically in
      PMP22-deficient (loss-of-function) mouse explants, the
      opposite direction from PMP22-duplication (gain-of-function)
      CMT1A, so it does not support a CMT1A supplementation trial.
  - reference: PMID:36511878
    reference_title: "Downregulation of PMP22 ameliorates myelin defects in iPSC-derived human organoid cultures of CMT1A."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Downregulation of PMP22 expression using short-hairpin RNAs or a combinatorial drug consisting of baclofen, naltrexone hydrochloride and D-sorbitol was able to ameliorate the myelin defects in CMT1A-organoids."
    explanation: >
      Patient-derived CMT1A iPSC-organoid rescue after PMP22
      downregulation is preclinical human-cell proof of concept for
      the PMP22-dosage axis, distinct from a human clinical trial.
  - reference: PMID:38017287
    reference_title: "AAV-mediated editing of PMP22 rescues Charcot-Marie-Tooth disease type 1A features in patient-derived iPS Schwann cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "decreased PMP22 gene duplication by 20-40%. Infection of CMT1A-iPSC-derived Schwann cell precursors with AAV2-hSaCas9-gRNAedit normalized PMP22 mRNA and PMP22 protein expression levels, and also ameliorated increased apoptosis and impaired myelination in CMT1A-iPSC-derived Schwann cells."
    explanation: >
      AAV-mediated editing of the PMP22 duplication rescued disease
      features in patient-derived CMT1A iPS Schwann cells —
      preclinical human-cell proof of concept, not yet a human trial.
  - reference: CGGV:assertion_ae6ffeae-9609-47bf-89a9-4863cf6ef05c-2026-06-12T160000.000Z
    reference_title: "KIF1B / Charcot-Marie-Tooth disease type 2A1 (Limited)"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "KIF1B | HGNC:16636 | Charcot-Marie-Tooth disease type 2A1 | MONDO:0007308 | AD | Limited | SOP12 | Charcot-Marie-Tooth Disease Gene Curation Expert Panel | 2026-06-12T16:00:00.000Z"
    explanation: >
      ClinGen's Charcot-Marie-Tooth Disease Gene Curation Expert
      Panel classifies the KIF1B-CMT2A1 gene-disease relationship as
      Limited (June 2026), so KIF1B should not be presented as
      equivalent in evidentiary weight to the established MFN2-CMT2A
      relationship. Graded PARTIAL because the assertion supports a
      downgrade of the KIF1B claim rather than the canonical model.
  - reference: PMID:26450076
    reference_title: "[Ascorbic Acid and Charcot-Marie-Tooth Disease]."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Based on these results, five clinical trials were undertaken at different centers worldwide. However, none of them demonstrated significant effectiveness."
    explanation: >-
      Substantiates the count and the outcome of the human ascorbic-acid
      programme asserted in the notes above. Classified HUMAN_CLINICAL because
      the evidence this review reports is the result of five human clinical
      trials, not a preclinical or consensus statement.
  - reference: PMID:21393063
    reference_title: "Ascorbic acid in Charcot-Marie-Tooth disease type 1A (CMT-TRIAAL and CMT-TRAUK): a double-blind randomised trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Ascorbic acid supplementation had no significant effect on neuropathy compared with placebo after 2 years, suggesting that no evidence is available to support treatment with ascorbic acid in adults with CMT1A."
    explanation: >-
      The largest and longest of those trials, and the direct source for the
      statement that human pharmacological attempts on the PMP22-dosage axis
      have so far been negative. It qualifies the translational arm of the
      canonical model, not its genetics: a failed ascorbate trial does not show
      that PMP22 dosage is the wrong target, only that this agent did not move
      the endpoint.
  - reference: PMID:25216747
    reference_title: "c-Jun activation in Schwann cells protects against loss of sensory axons in inherited neuropathy."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "The results indicate that c-Jun elevation in the Schwann cells of C3 nerves serves to prevent loss of myelinated sensory axons, particularly in distal nerves, improve behavioural symptoms, and preserve F-wave persistence."
    explanation: >-
      Conditional inactivation of Schwann-cell c-Jun in the C3-PMP22 CMT1A
      mouse worsened distal sensory axon loss, so the same cell that carries
      the genetic lesion also mounts a protective repair programme against the
      shared terminal node. Length-dependent axonal degeneration is therefore
      a modulated outcome in this model rather than an inevitable consequence
      of the myelin defect.
  - reference: PMID:28796392
    reference_title: "Natural history of Charcot-Marie-Tooth disease during childhood."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Participants with CMT2A progressed faster than CMT1A (mean difference, -4.4; 95% CI, -8.1 to -0.8; p = 0.02)."
    explanation: >-
      Two-year longitudinal CMTPedS data from 206 children show that genetic
      subtype predicts rate of decline, so convergence of CMT1A and CMT2A on a
      shared terminal node does not imply a shared disease course. Qualifies
      the final-common-pathway framing with human, not model, data.
  - reference: PMID:38743588
    reference_title: "PMP22 duplication dysregulates lipid homeostasis and plasma membrane organization in developing human Schwann cells."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Furthermore, we identified reduced lipid raft dynamics, disturbed plasma membrane fluidity and impaired cholesterol incorporation and storage, all of which could result from altered lipid storage homeostasis in the patient-derived CMT1A iPSC-SCPs."
    explanation: >-
      Extends the PMP22 cholesterol branch of refinement (6) into the
      duplication (gain-of-function) direction and into patient-derived human
      Schwann cell precursors. This is the direction the PMP22-deficient
      explant supplementation rescue does not address, so it supports the
      lipid-handling mechanism without supporting a supplementation strategy
      for CMT1A.
phenotypes:
- category: Neurologic
  name: Distal Muscle Weakness
  diagnostic: true
  phenotype_term:
    preferred_term: Distal muscle weakness
    term:
      id: HP:0002460
      label: Distal muscle weakness
    clinical_course: PROGRESSIVE
- category: Musculoskeletal
  name: Pes Cavus
  phenotype_term:
    preferred_term: Pes cavus
    term:
      id: HP:0001761
      label: Pes cavus
- category: Neurologic
  name: Decreased Tendon Reflexes
  phenotype_term:
    preferred_term: Hyporeflexia
    term:
      id: HP:0001265
      label: Hyporeflexia
- category: Neurologic
  name: Distal Sensory Loss
  phenotype_term:
    preferred_term: Distal sensory impairment
    term:
      id: HP:0002936
      label: Distal sensory impairment
biochemical:
- name: Plasma Neurofilament Light Chain
  biomarker_term:
    preferred_term: plasma neurofilament light chain
    term:
      id: NCIT:C88043
      label: Neurofilament Light Polypeptide
  presence: Elevated relative to controls
  context: >-
    Genetically confirmed CMT of mixed subtype versus matched controls,
    measured in plasma by single-molecule array.
  notes: >-
    NfL reports on the shared terminal node of CMT, axonal loss, rather than on
    any one causative gene, which is why it is curated on this umbrella entry
    instead of a subtype entry. It correlates with cross-sectional severity but
    has never been shown to move in response to an effective disease-modifying
    therapy, so it is not a validated surrogate endpoint; see the
    biomarker-responsiveness knowledge gap below.
  evidence:
  - reference: PMID:39882365
    reference_title: "Evaluating plasma biomarkers NfL, GFAP, GDF15, and FGF21 as indicators of disease severity in Charcot-Marie Tooth patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "NfL and GFAP levels were correlated with the CMTNSv2 score (rs = 0.46, p = 0.002; rs = 0.31, p = 0.04)."
    explanation: >-
      In 44 genetically confirmed CMT patients and 44 matched controls, plasma
      NfL correlated with the CMT Neuropathy Score version 2. The correlation
      is moderate and cross-sectional, so it supports NfL as a severity
      indicator rather than as a progression or treatment-response measure.
- name: Plasma Glial Fibrillary Acidic Protein
  presence: Elevated relative to controls
  context: >-
    Genetically confirmed CMT of mixed subtype versus matched controls,
    measured in plasma by single-molecule array.
  notes: >-
    GFAP is an astroglial protein, so its elevation in a peripheral neuropathy
    is not straightforward to attribute; the source study reports the
    association without demonstrating a glial lesion in nerve. No NCI Thesaurus
    biomarker term for GFAP was present in this repository's term cache at
    curation time, so this entry deliberately carries no bound term rather than
    a guessed CURIE.
  evidence:
  - reference: PMID:39882365
    reference_title: "Evaluating plasma biomarkers NfL, GFAP, GDF15, and FGF21 as indicators of disease severity in Charcot-Marie Tooth patients."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In the group of patients with CMT, the concentrations of GDF15, FGF21, NfL, and GFAP were significantly higher than in the control group (p < 0.05)."
    explanation: >-
      Establishes that plasma GFAP is raised in CMT relative to controls in
      this 44-case, 44-control study. The study does not localise the glial
      signal, so the elevation is curated as an observed association only.
genetic:
- name: PMP22
  gene_term:
    preferred_term: PMP22
    term:
      id: hgnc:9118
      label: PMP22
  association: Causal
  notes: >-
    PMP22 (peripheral myelin protein 22) is the dominant CMT gene. A 1.4 Mb
    tandem duplication causes CMT1A (the single most common CMT genotype);
    a reciprocal deletion of the same region causes HNPP. Point mutations
    in PMP22 cause rarer demyelinating forms.
  evidence:
  - reference: DOI:10.1093/brain/awae064
    reference_title: "Whole genome sequencing increases the diagnostic rate in Charcot-Marie-Tooth disease"
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The most common genetic diagnosis was PMP22 duplication (CMT1A; 505/1165, 43.3%), then GJB1 (CMTX1; 151/1165, 13.0%), PMP22 deletion (HNPP; 72/1165, 6.2%) and MFN2 (CMT2A; 46/1165, 3.9%)"
    explanation: PMP22 duplication (43.3%) and deletion (6.2%) together drive nearly half of all genetically resolved CMT.
- name: GJB1
  gene_term:
    preferred_term: GJB1
    term:
      id: hgnc:4283
      label: GJB1
  association: Causal
  notes: >-
    GJB1 encodes connexin-32, expressed in Schwann cells at the paranodal
    gap junctions. X-linked dominant / semidominant (CMTX1): males are more
    severely affected, but heterozygous carrier females are commonly
    symptomatic. The second most common genetic cause of CMT.
- name: MFN2
  gene_term:
    preferred_term: MFN2
    term:
      id: hgnc:16877
      label: MFN2
  association: Causal
  notes: >-
    MFN2 (mitofusin 2) mutations cause axonal CMT2A, the dominant CMT2
    subtype. MFN2 is required for mitochondrial fusion and mitochondrial
    axonal transport.
- name: MPZ
  gene_term:
    preferred_term: MPZ
    term:
      id: hgnc:7225
      label: MPZ
  association: Causal
  notes: >-
    MPZ (myelin protein zero) is the most abundant peripheral myelin
    protein. Mutations cause CMT1B and a subset of CMT2 forms; many
    mutations trigger protein misfolding, UPR, and chronic ER stress
    in Schwann cells.
treatments:
- name: Physical and Occupational Therapy
  description: Mainstay of supportive care to maintain mobility and function.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
- name: Orthotic Bracing
  description: Ankle-foot orthoses to compensate for foot drop and improve gait.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
- name: Genetic Counseling
  description: Counseling for affected individuals and families.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
- name: PXT3003
  description: >-
    Oral fixed-dose combination of low-dose baclofen, naltrexone, and
    sorbitol designed to lower PMP22 expression and improve axonal
    function in CMT1A. Phase III trials (PLEO-CMT NCT02579759 completed,
    PREMIER NCT04762758).
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: baclofen
      term:
        id: CHEBI:2972
        label: baclofen
    - preferred_term: naltrexone
      term:
        id: CHEBI:7465
        label: naltrexone
  evidence:
  - reference: DOI:10.3390/genes14071391
    reference_title: "The Current State of Charcot–Marie–Tooth Disease Treatment"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Compounds such as PXT3003, which are being clinically and preclinically investigated, and a broad array of therapeutic agents and their corresponding mechanisms are discussed."
    explanation: Establishes PXT3003 as an active clinical/preclinical therapeutic candidate for CMT.
  - reference: PMID:34656144
    reference_title: "A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot-Marie-Tooth type 1A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The high-dose group demonstrated a statistically significant improvement in the primary endpoint and a good safety profile."
    explanation: >-
      PLEO-CMT phase III result in 323 adults with mild-to-moderate CMT1A. The
      high-dose arm beat placebo on the Overall Neuropathy Limitations Scale
      (mean difference 0.37 points, p = 0.008). This is the only positive
      pharmacological trial in CMT1A to date and the effect size is small.
  - reference: PMID:34656144
    reference_title: "A double-blind, placebo-controlled, randomized trial of PXT3003 for the treatment of Charcot-Marie-Tooth type 1A."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The high-dose group was discontinued early due to unexpected crystal formation in the high-dose formulation, which resulted in an unanticipated high discontinuation rate, overall and especially in the high-dose group."
    explanation: >-
      Records the conduct problem that qualifies the result above: the arm that
      produced the positive finding was stopped early for formulation
      crystallization, and the statistical analysis plan was adapted before
      database lock to handle the resulting missing data. The trial supports
      PXT3003 as promising, not as established disease-modifying therapy.
- name: AAV9-MFN2 Gene Therapy
  description: >-
    Intrathecal delivery of an AAV9 vector expressing MFN2 to restore ER-mitochondria contacts
    and prevent axonal degeneration in CMT2A. In vivo studies demonstrate therapeutic efficacy
    even when administered after symptom onset, with good tolerability profile.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  evidence:
  - reference: PMID:42301793
    reference_title: "Restoring the interplay between the endoplasmic reticulum and mitochondria by gene therapy improves Charcot-Marie-Tooth type 2A disease"
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Intrathecal delivery of an AAV9 vector expressing MFN2WT effectively targets motor and sensory neurons, restoring ER-mitochondria contacts and mitochondrial morphology, thereby preserving both neuromuscular junction integrity and motor function"
    explanation: Demonstrates that AAV9-MFN2 gene therapy restores ER-mitochondria contact homeostasis and prevents axonal degeneration in transgenic CMT2A models and patient-derived motor neurons.
- name: PMP22-Lowering Antisense Oligonucleotide
  description: >-
    Investigational antisense oligonucleotides that suppress PMP22 mRNA in
    affected peripheral nerve, addressing the causal gene-dosage lesion of
    CMT1A rather than a downstream consequence of it. The published rodent
    proof of concept used 16-mer chimeric gapmer phosphorothioate
    oligonucleotides carrying constrained-ethyl residues at positions 1 to 3
    and 14 to 16, acting through RNase H-mediated degradation of the target
    transcript. Preclinical only: no human trial of direct PMP22 lowering has
    reported results, which is this entry's central translational gap.
  therapeutic_modality: ANTISENSE_OLIGONUCLEOTIDE
  aso_details:
    aso_mechanism: RNASE_H_KNOCKDOWN
    target_gene:
      preferred_term: PMP22
      term:
        id: hgnc:9118
        label: PMP22
    target_transcript: PMP22 mRNA
    aso_chemistry: CONSTRAINED_ETHYL
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  evidence:
  - reference: PMID:29202483
    reference_title: "PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Notably, initiation of ASO treatment after disease onset restored myelination, MNCV, and CMAP almost to levels seen in WT animals."
    explanation: >-
      Post-onset dosing reversed myelination and nerve-conduction deficits in
      two rodent CMT1A models. Because treatment started after disease was
      established, this is the strongest preclinical argument that the PMP22
      dosage lesion drives an ongoing, reversible process rather than only a
      fixed developmental one. Rodent models only.
  - reference: PMID:29202483
    reference_title: "PMP22 antisense oligonucleotides reverse Charcot-Marie-Tooth disease type 1A features in rodent models."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Furthermore, we demonstrated that reduction of PMP22 mRNA in skin biopsies from ASO-treated rats is a suitable biomarker for evaluating target engagement in response to ASO therapy."
    explanation: >-
      Establishes skin-biopsy PMP22 mRNA as the target-engagement readout
      proposed for a first-in-human PMP22-lowering trial, which is the measure
      the discriminating test in the knowledge gap below depends on.
- name: AAV9-miR871 PMP22 Silencing Gene Therapy
  description: >-
    Lumbar intrathecal AAV9 delivering a U6-driven artificial microRNA
    (miR871) that silences PMP22 mRNA in Schwann cells, developed as a
    one-time treatment for CMT1A. Preclinical: efficacy in a humanized CMT1A
    mouse model, with dose ranging, toxicity, and vector biodistribution work
    in mice and non-human primates assembled to support a first-in-human
    trial.
  therapeutic_modality: GENE_THERAPY
  treatment_term:
    preferred_term: gene therapy
    term:
      id: NCIT:C15238
      label: Gene Therapy
  evidence:
  - reference: PMID:41948127
    reference_title: "Safety, efficacy, and distal nerve Schwann cell biodistribution in mice and NHPs to support translation of AAV9 RNAi therapy for CMT1A."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A single injection produced long-term miR871 expression, triggered selective RNA interference against the PMP22 mRNA, and subsequently lowered protein levels and improved disease manifestations in a humanized CMT1A model."
    explanation: >-
      Single-dose intrathecal AAV9 achieved sustained, selective PMP22
      knockdown and phenotypic improvement in a humanized CMT1A mouse,
      independently corroborating the ASO result that lowering PMP22 modifies
      established disease in rodents.
  - reference: PMID:41948127
    reference_title: "Safety, efficacy, and distal nerve Schwann cell biodistribution in mice and NHPs to support translation of AAV9 RNAi therapy for CMT1A."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "We found vector biodistribution and miR871 expression in distal peripheral nerves, PMP22 target engagement in mice and NHPs, and silencing to levels expected to support normal myelination in humans."
    explanation: >-
      Reaching distal peripheral nerve is the delivery problem specific to a
      length-dependent neuropathy, and target engagement was shown in
      non-human primates as well as mice. The human silencing level is
      extrapolated, not measured, so this supports translational readiness and
      not human efficacy.
prevalence:
- population: Auckland region, New Zealand (population-based multi-source ascertainment)
  measure_type: POINT_PREVALENCE
  prevalence_class: BAND_1_5_PER_10000
  rate_per_100000: 15.7
  rate_low: 11.6
  rate_high: 21.0
  notes: >-
    Age-standardised point prevalence from a population-based study using multiple
    case ascertainment sources (primary care, hospitals, neuromuscular disease registry,
    community organisations, self-referral) in the Auckland Region of New Zealand, 2016.
    Highest prevalence was in the 50–64 age group (25.2/100,000). Estimates from single
    ascertainment sources may underestimate true prevalence. The commonly cited "1 in 2,500"
    figure (40/100,000) likely reflects earlier clinical-series estimates and may include
    broader ascertainment; the NZ population-based rate is lower.
  evidence:
  - reference: PMID:31203252
    reference_title: "Prevalence of Charcot-Marie-Tooth disease across the lifespan: a population-based epidemiological study."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Age-standardised point prevalence of all CMT cases was 15.7 per 100 000"
    explanation: >-
      Population-based study using multiple ascertainment sources in the Auckland Region
      of New Zealand reports an age-standardised point prevalence of 15.7 per 100,000
      (95% CI 11.6–21.0) for all CMT.
references:
- reference: PMID:20301532
  title: "Charcot-Marie-Tooth Hereditary Neuropathy Overview."
  tags:
  - GeneReviews
  findings: []
datasets:
discussions:
- discussion_id: human_proof_of_concept_pmp22_lowering
  prompt: >-
    Does lowering PMP22 modify disease in people with CMT1A, as it does in
    rodent models?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - mechanistic_hypotheses#canonical_pmp22_mpz_axonal_demyelinating_neuropathy_model
  - treatments#PMP22-Lowering Antisense Oligonucleotide
  - treatments#AAV9-miR871 PMP22 Silencing Gene Therapy
  rationale: >-
    The PMP22 dosage axis is the load-bearing claim of the canonical model and
    is validated only in rodents and in patient-derived cells. Antisense
    oligonucleotide and AAV9-miRNA approaches both improve established disease
    in rodent CMT1A models, and PMP22 downregulation rescues myelin defects in
    patient-derived organoids and iPS Schwann cells, but no human trial of
    direct PMP22 lowering has reported results. Every agent actually given to
    people with CMT1A has acted indirectly: five ascorbic-acid trials were
    negative, and PXT3003 is a three-drug combination whose modest phase III
    benefit cannot be attributed to PMP22 lowering specifically. Until a
    first-in-human trial of direct lowering reads out, the axis is a
    preclinical inference rather than a demonstrated human mechanism.
  proposed_experiments:
  - experiment_id: exp_cmt_first_in_human_pmp22_lowering
    name: First-in-human dose-escalation trial of direct PMP22 lowering in CMT1A
    description: >-
      Phase 1/2 dose escalation in adults with genetically confirmed CMT1A of
      mild to moderate severity, using either a PMP22 antisense oligonucleotide
      or an intrathecal AAV9-miRNA vector. Pair target engagement, measured as
      PMP22 mRNA in serial skin biopsies, with the two outcome measures that
      have shown movement over 12 months in this disease: quantitative calf
      muscle MRI fat fraction and plasma neurofilament light chain.
    decision_criterion: >-
      Dose-dependent reduction of skin PMP22 mRNA accompanied by stabilisation
      of calf muscle fat fraction and of plasma NfL against the untreated
      natural-history trajectory would establish PMP22 dosage as a modifiable
      human mechanism.
    would_support:
    - mechanistic_hypotheses#canonical_pmp22_mpz_axonal_demyelinating_neuropathy_model
    would_refute:
    - mechanistic_hypotheses#canonical_pmp22_mpz_axonal_demyelinating_neuropathy_model
    supporting_outcome:
    - >-
      Skin PMP22 mRNA falls dose-dependently, and calf muscle fat fraction and
      plasma NfL stabilise relative to the natural-history trajectory.
    refuting_outcome:
    - >-
      Skin PMP22 mRNA falls to the degree that rescues rodent models while calf
      muscle fat fraction and plasma NfL continue on their untreated
      trajectory, indicating that PMP22 dosage is not rate-limiting for
      established human disease.
  evidence:
  - reference: PMID:41948127
    reference_title: "Safety, efficacy, and distal nerve Schwann cell biodistribution in mice and NHPs to support translation of AAV9 RNAi therapy for CMT1A."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "To support clinical translation, we confirmed on-target specificity of miR871 for PMP22 in vitro, identified a safe and effective dosing range in mice, demonstrated absence of significant toxicity in rodents and non-human primates (NHPs), and performed a detailed AAV biodistribution study in a large animal model."
    explanation: >-
      The most advanced direct-lowering programme describes its own package as
      work done to support clinical translation, which is a statement that the
      human step has not yet been taken.
- discussion_id: cmt_biomarker_response_to_therapy
  prompt: >-
    Has any CMT biomarker been shown to change in response to an effective
    disease-modifying therapy?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - biochemical#Plasma Neurofilament Light Chain
  - biochemical#Plasma Glial Fibrillary Acidic Protein
  rationale: >-
    Quantitative calf muscle MRI fat fraction, plasma NfL, and plasma GFAP all
    separate CMT from controls and track severity, and fat fraction moves
    enough over 12 months to be proposed as a trial endpoint. None has been
    measured against a therapy that works, because until PXT3003 no CMT therapy
    did, and PXT3003 was not run with these readouts. Responsiveness to
    untreated progression is necessary but not sufficient for surrogacy: a
    marker can track decline faithfully and still fail to move when the
    upstream mechanism is corrected. Treating any of these as a validated
    surrogate endpoint would overstate what has been shown, and the biomarker
    substudy belongs inside the first direct-lowering trial rather than after
    it.
  evidence:
  - reference: PMID:39957630
    reference_title: "Twelve-month change in quantitative MRI calf muscle fat fraction in CMT1A predicts clinical change over 4 years."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We demonstrated a consistent progression of calf muscle MRI fat over 4 years, significant longitudinal correlation between CMT Examination Score and calf muscle fat, and potential as a bridging biomarker by 1 year change in fat correlating with long-term clinical progression."
    explanation: >-
      The strongest responsiveness result available for any CMT biomarker, from
      20 untreated CMT1A patients followed for a mean of four years. The
      authors claim potential as a bridging biomarker rather than demonstrated
      surrogacy, which is the boundary this gap records.
📚

References & Deep Research

References

1
PMID:20301532
Charcot-Marie-Tooth Hereditary Neuropathy Overview.
No top-level findings curated for this source.

Deep Research

1

Deep research results are used as seeds for research; they do not undergo the same validation as the main records and may contain errors. How we use deep research.

Evaluations and curation notes (1)

Reconcile canonical PMP22/MPZ hypothesis notes with independent OpenScientist assessment (#7405) · 2026-08-03T21:13:59Z · View source

Rewrote the canonical_pmp22_mpz_axonal_demyelinating_neuropathy_model hypothesis's notes field to replace six copied, overreaching report-level claims with source-, model-, subtype-, and species-scoped statements per issue #7405's independent reconciliation of the 2026 openscientist deep-research report (sidecar assessment merged in PR #7406). Corrected: (1) blended '43-60%' PMP22-duplication frequency range now split into the correct diagnosed-case denominators (505/1165=43.3%, 505/1515=33.3%, PMID:38481354) versus the non-comparable background ~60% figure (PMID:31852984); (2) absolute 'DYSMYELINATING NOT demyelinating' claim softened to a coexisting developmental component (PMID:19923170, PMID:21487305); (3)-(4) structural-organizer/UPR/SARM1 claims scoped to their actual source models (CMT1A+HNPP mice PMID:41400104; C3-PMP22/MpzR98C mice PMID:35501630; one Mfn2-H361Y rat PMID:36287202) instead of generalized across CMT; (5) macrophage-CSF1 neuroinflammation scoped to CMT1B/CMT1X models (PMID:16775375, PMID:26865613) and the terminal-complement-inhibition item (PMID:36926597) corrected from a listed 'failed human trial' to what it actually is, a mouse experiment; (6) cholesterol-supplementation rescue corrected to its actual direction (PMP22-deficient/loss-of-function mice, PMID:32511821), which does not support a CMT1A (gain-of-function/duplication) supplementation trial; and the human proof-of-concept gap reframed to note real preclinical human-cell (iPSC-organoid/iPS-Schwann-cell) rescue data (PMID:36511878, PMID:38017287) rather than stating the entire human dosage axis is unvalidated. Two of the issue's eight items (KIF1B attribution; the '128-paper/36-finding' provider-provenance claim) were confirmed to concern only the provider report/assessment sidecar, not any current assertion in this disease YAML, so no change was needed for those two. Added 12 new evidence items (one per newly-cited PMID) with exact-quote snippets verified against freshly fetched references_cache/*.md abstracts, each with an evidence_source classification (HUMAN_CLINICAL/MODEL_ORGANISM/IN_VITRO) and an explanation tying it to the specific scoped claim. status: CANONICAL is unchanged -- this is a scoping correction, not a verdict change. Validated with just validate (schema + term + reference, 14/14 new-PMID snippets verified) and a targeted pytest -k 'Charcot or hypothesis or evidence' run (3822 passed).

Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 32 citations 2026-05-12T17:46:44.508259

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Charcot-Marie-Tooth Disease
  • MONDO ID: (if available)
  • Category: Mendelian

Research Objectives

Please provide a comprehensive research report on Charcot-Marie-Tooth Disease covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Disease Characteristics Report: Charcot–Marie–Tooth Disease (CMT)

Target disease: Charcot–Marie–Tooth disease (CMT) (hereditary motor and sensory neuropathy spectrum; Mendelian).

Evidence note / limitations: The tool-accessible corpus for this run contains high-quality peer‑reviewed clinical genetics, outcomes, and treatment/trial sources (2023–2024 emphasized), but it does not include direct pulls from OMIM/Orphanet/MeSH/MONDO authority pages. Therefore, formal identifiers (OMIM/ORPHA/MeSH/MONDO/ICD) cannot be reliably populated from this evidence set and are flagged as not available from retrieved sources.

1. Disease Information

1.1 Concise overview

Charcot–Marie–Tooth disease (CMT) is among the most common inherited peripheral neuropathies and is genetically heterogeneous, with reports of >130 disease-causing genes in modern diagnostic series. (record2024wholegenomesequencing pages 1-2)

CMT and related inherited neuropathies are commonly classified clinically/electrophysiologically into demyelinating (CMT1), axonal (CMT2), and intermediate forms, with additional related categories such as hereditary motor neuropathy (HMN), hereditary sensory neuropathy (HSN), and hereditary neuropathy with liability to pressure palsies (HNPP). In a large specialist-center cohort (2009–2023; n=1515), the clinical distribution included CMT1 41.0%, CMT2 19.4%, intermediate CMT 13.5%, HMN 9.2%, HSN 6.1%, HNPP 4.8%, and others. (record2024wholegenomesequencing pages 1-2)

1.2 Common synonyms / alternate names

Within this evidence set, CMT is discussed under: - Charcot–Marie–Tooth disease (CMT) - CMT1A (most common genetic subtype; PMP22 duplication) - CMTX1 (GJB1) - HNPP (PMP22 deletion) - “inherited peripheral neuropathies / inherited neuropathies” (umbrella term used in therapeutic and modeling literature) (record2024wholegenomesequencing pages 1-2, okamoto2023thecurrentstate pages 1-2, mandarakas2024multicentervalidationof pages 1-2)

1.3 Key identifiers (OMIM, Orphanet, ICD, MeSH, MONDO)

Not extractable from the retrieved evidence in this run; requires direct querying of OMIM/Orphanet/MONDO/MeSH/ICD sources.

1.4 Evidence source type

Most information in this report is derived from: - Aggregated disease-level resources (large specialty-center series; multicenter validation cohorts; reviews). (record2024wholegenomesequencing pages 1-2, okamoto2023thecurrentstate pages 1-2, mandarakas2024multicentervalidationof pages 1-2) - Clinical trial registry records (ClinicalTrials.gov). (NCT04762758 chunk 1, NCT06328712 chunk 1, NCT02579759 chunk 1, NCT05361031 chunk 2, NCT03023540 chunk 2)

2. Etiology

2.1 Disease causal factors

CMT is primarily a genetic disorder caused by pathogenic variants affecting peripheral nerve myelination (Schwann-cell biology) and/or axonal structure/function.

Across modern clinical cohorts, the most common genetic causes are: - PMP22 duplication (CMT1A) - GJB1 variants (CMTX1) - PMP22 deletion (HNPP) - MFN2 variants (CMT2A) (record2024wholegenomesequencing pages 1-2)

In the 1515-patient Brain 2024 specialist series, among solved cases (n=1165), the leading diagnoses were PMP22 duplication 43.3%, GJB1 13.0%, PMP22 deletion 6.2%, MFN2 3.9%. (record2024wholegenomesequencing pages 1-2)

2.2 Risk factors

Genetic risk

The dominant “risk factor” is carrying a pathogenic germline variant in one of many CMT genes. The contribution of a small number of genes is particularly large: a 2023 diagnostic study emphasizes that PMP22, GJB1, MFN2, and MPZ account for “nearly 80%” of genetically inherited CMT in their summary framing. (ceylan2023highdiagnosticyield pages 1-2)

Environmental / non-genetic risk factors

The available evidence set does not contain robust epidemiologic analyses of environmental contributors to CMT onset; however, CMT severity can be affected by clinical course and management and potentially by exposures that worsen neuropathy (e.g., avoidance of neurotoxic medications is referenced as an exclusion in a long-term PXT3003 extension protocol). (NCT03023540 chunk 2)

2.3 Protective factors

No protective genetic or environmental factors were identified in the retrieved evidence set.

2.4 Gene–environment interactions

Direct gene–environment interaction studies were not present in the retrieved evidence.

3. Phenotypes

3.1 Core phenotype spectrum (high-level)

Although phenotype is heterogeneous, commonly highlighted clinical manifestations include distal weakness and sensory impairment with functional limitations. Subtype-specific cohorts demonstrate additional features (e.g., in CMT4J). (record2024wholegenomesequencing pages 1-2)

Example: CMT4J (FIG4-related) clinical features

A 2024 Neurology cross-sectional cohort (n=19; 14 pediatric, 5 adult) reported: - Most frequent neuromuscular symptoms: gross motor delay and distal > proximal muscle weakness (14/19). - Most common non-neuromuscular symptoms: cognitive and respiratory deficits (each 8/19). - Nonuniform slowing of conduction velocities in 6 patients; asymmetric weakness in 2 patients. - CMTPedS and QoL/adaptive behavior scales affected in most patients; neurofilament light correlated with CMTPedS in pediatrics. (mandarakas2024multicentervalidationof pages 5-6)

3.2 Phenotype characteristics (onset, progression, severity)

CMT is typically chronic and slowly progressive; formal onset/progression metrics vary by genotype and are not comprehensively quantified in the extracted evidence set. However, CMT4J demonstrates childhood disease burden with motor delay and multisystem features. (mandarakas2024multicentervalidationof pages 5-6)

3.3 Quality of life impact

The CMT functional burden is captured in validated functional measures such as the CMT-FOM (adult CMT1A), which discriminates patients by self-reported trips/falls, unsteady ankles, tremor, and hand weakness. (mandarakas2024multicentervalidationof pages 1-2)

3.4 Suggested HPO terms (non-exhaustive; ontology mapping suggestions)

The evidence set supports mapping to common CMT manifestations; suggested HPO terms include: - Distal muscle weakness (HP:0002460) - Muscle atrophy (HP:0003202) - Pes cavus (HP:0001761) - Areflexia (HP:0001284) - Peripheral neuropathy (HP:0009830) - Gait abnormality (HP:0001288) - Gross motor delay (HP:0002194) — particularly supported in CMT4J (mandarakas2024multicentervalidationof pages 5-6) - Respiratory insufficiency (HP:0002093) and Cognitive impairment (HP:0100543) — supported for CMT4J (mandarakas2024multicentervalidationof pages 5-6)

(These HPO IDs are ontology suggestions; they are not explicitly listed in the retrieved sources and should be verified against HPO.)

4. Genetic / Molecular Information

4.1 Causal genes (high-frequency examples)

Large contemporary diagnostic work shows that a limited set of genes accounts for a substantial fraction of diagnoses: - PMP22: duplication → CMT1A; deletion → HNPP (record2024wholegenomesequencing pages 1-2) - GJB1: CMTX1 (record2024wholegenomesequencing pages 1-2) - MFN2: CMT2A (record2024wholegenomesequencing pages 1-2)

A 2023 review further summarizes that, among positive molecular findings in a large commercial dataset, PMP22 duplications and deletions dominated, with next most frequent positives in GJB1, MPZ, MFN2, and that 94.9% of positives were in PMP22/GJB1/MPZ/MFN2. (okamoto2023thecurrentstate pages 1-2)

4.2 Pathogenic variant classes

Common variant classes implicated in CMT include: - Copy-number variants (CNVs), particularly PMP22 duplication (CMT1A) and PMP22 deletion (HNPP), typically detected via MLPA or similar assays. (ceylan2023highdiagnosticyield pages 1-2, ceylan2023highdiagnosticyield pages 2-4, record2024wholegenomesequencing pages 2-3) - Single nucleotide variants and small indels across many genes, increasingly detected by targeted NGS panels, WES, and WGS with ACMG-based classification. (record2024wholegenomesequencing pages 1-2, ceylan2023highdiagnosticyield pages 1-2)

4.3 Modifier genes / epigenetics

The retrieved evidence set does not provide definitive modifier-gene or epigenetic mechanisms for CMT at a knowledge-base-ready level.

5. Environmental Information

No disease-specific environmental causal factors were identified in the retrieved evidence set. Environmental relevance is most clearly implicit through avoidance of concomitant neurotoxic drugs in trial protocols and through supportive care/rehabilitation. (NCT03023540 chunk 2)

6. Mechanism / Pathophysiology

6.1 Core mechanistic principles across common subtypes

PMP22 overexpression (CMT1A)

A major disease mechanism in CMT1A is increased PMP22 dosage (duplication), motivating disease-modifying strategies aiming to downregulate PMP22 (siRNA, ASO, AAV-mediated silencing) and to improve axonal function. (okamoto2023thecurrentstate pages 16-17, NCT02579759 chunk 1)

MPZ (CMT1B)

A 2024 review focused on CMT1B describes that MPZ mutations can lead to protein misfolding, UPR activation, ER stress, or mistrafficking, motivating approaches such as gene therapy and proteostasis modulation (review-level mechanistic framing). (mcculloch2024navigatingthelandscape pages 22-23)

Inflammation as a potential co-mechanism

A 2024 perspective review notes that inflammation and neurodegeneration may coexist in some CMTs and discusses implications for immunomodulatory approaches in selected patients. (yalcouye2023geneticsofhearing pages 163-166)

6.2 Pathways / processes / ontology suggestions

Supported or strongly implied mechanisms include: - Myelination / Schwann cell biology (GO:0042552 myelination; CL:0000218 Schwann cell) - Axon maintenance and degeneration (GO:0007409 axonogenesis; GO:0008050 axon guidance) - ER stress / unfolded protein response for MPZ-related disease (GO:0030968 endoplasmic reticulum unfolded protein response)

(These GO/CL suggestions should be validated against ontology references; not enumerated directly in the retrieved sources.)

7. Anatomical Structures Affected

Primary system: peripheral nervous system (peripheral nerves; motor and sensory fibers). (record2024wholegenomesequencing pages 1-2)

Key tissue/cell types implicated by the genetic targets and mechanistic discussions: - Peripheral nerves (UBERON:0000010 peripheral nerve) - Schwann cells (CL:0000218) - Peripheral neurons / axons (CL:0000540 neuron; GO cellular components such as axon)

8. Temporal Development

CMT is chronic and typically slowly progressive across many subtypes, creating challenges for detecting change in clinical trials and motivating sensitive outcome measures and biomarkers. (okamoto2023thecurrentstate pages 12-14, mandarakas2024multicentervalidationof pages 1-2)

9. Inheritance and Population

9.1 Epidemiology

Modern sources in this evidence set provide broad prevalence ranges: - A large specialist diagnostic cohort cites estimated prevalence 1 in 2,500 to 1 in 10,000. (record2024wholegenomesequencing pages 1-2) - A 2023 treatment review states incidence on the order of ~10–40 per 100,000 (as reported in that review). (okamoto2023thecurrentstate pages 1-2)

9.2 Subtype frequencies (genetic)

In the Brain 2024 specialist cohort, among solved cases (n=1165) the most common diagnoses were: - PMP22 duplication (CMT1A): 43.3% - GJB1 (CMTX1): 13.0% - PMP22 deletion (HNPP): 6.2% - MFN2 (CMT2A): 3.9% (record2024wholegenomesequencing pages 1-2)

10. Diagnostics

10.1 Current understanding: tiered genetic testing is central

A consistent theme across 2023–2024 evidence is the value of an algorithmic, tiered testing strategy: - First tier: targeted PMP22 CNV detection (e.g., MLPA) given high prevalence of duplication/deletion. - Second tier: targeted NGS gene panels. - Escalation: WES/WGS (often via virtual panels) and multidisciplinary review, particularly for unsolved cases. (ceylan2023highdiagnosticyield pages 1-2, record2024wholegenomesequencing pages 2-3)

10.2 Diagnostic yield statistics

MLPA, panel NGS, WES (single-center algorithmic series)

In a 2023 hereditary neuropathy series (n=64 suspected CMT): - MLPA diagnosed 39% (25/64) (14 duplications, 11 deletions). - In those proceeding to targeted NGS panels, yield was 36% (18/50). - WES solved 80% (4/5) of panel-negative cases. (ceylan2023highdiagnosticyield pages 1-2, ceylan2023highdiagnosticyield pages 2-4)

Large specialist-center yield and contribution of WGS

In the Brain 2024 specialist cohort (n=1515): - Overall genetic diagnosis rate 76.9% (1165/1515). - WGS in the UK 100,000 Genomes Project subgroup had a “true” diagnostic rate 19.7% (46/233); overall WGS “uplift” for the entire cohort was 3.5%. (record2024wholegenomesequencing pages 1-2)

10.3 Outcome measures in clinical evaluation

The Brain 2024 cohort notes use of validated scales including CMT Examination Score and CMT Neuropathy Score in phenotyping. (record2024wholegenomesequencing pages 1-2)

11. Outcome / Prognosis

Robust survival and life expectancy statistics were not present in the retrieved evidence set. The disease burden is better captured by validated functional scales and quality-of-life impact.

11.1 Validated outcome measures (2024 update)

CMT-FOM (adult CMT1A)

A 2024 multicenter validation established the CMT-Functional Outcome Measure (CMT-FOM) for adult CMT1A (PMP22 duplication): - Cohort: n=214, ages 18–75, 58% female across US/UK/Italy. (mandarakas2024multicentervalidationof pages 1-2) - Structure: 12-item, ~30 minutes, 0–100 interval score (0 unaffected → 100 severe). (mandarakas2024multicentervalidationof pages 1-2, mandarakas2024multicentervalidationof pages 6-9) - Psychometrics: excellent interrater reliability ICC 0.992; convergent validity with CMTES-R (r=0.643) and ONLS (r=0.516). (mandarakas2024multicentervalidationof pages 1-2, mandarakas2024multicentervalidationof pages 6-9)

12. Treatment

12.1 Current standard of care (real-world implementation)

No disease-curative pharmacotherapy is established in the evidence set; current management is largely symptomatic/supportive and includes multidisciplinary approaches. Reviews emphasize the absence of definitive pharmacologic treatment and the need for sensitive endpoints due to slow progression. (okamoto2023thecurrentstate pages 12-14)

12.2 Disease-modifying and advanced therapeutics (pipeline)

(A) PXT3003 (fixed-dose combination; oral)

What it is: PXT3003 is described in Phase III trials as an oral fixed-dose combination of (RS)-baclofen, naltrexone HCl, and D-sorbitol intended to limit PMP22 production and protect/improve axonal function (trial registry description). (NCT04762758 chunk 1, NCT02579759 chunk 1)

Key trials (ClinicalTrials.gov): - PLEO-CMT (NCT02579759): Phase 3, randomized, double-blind, placebo-controlled; enrollment 323; completed. Primary endpoint: mean ONLS at months 12 and 15; included 10MWT and CMTNS-v2 derived measures among secondary endpoints; a quality issue caused premature discontinuation of one dose arm in 2017. (NCT02579759 chunk 1) - PREMIER (NCT04762758): Phase 3, randomized, double-blind; planned ~350; status reported as active not recruiting; primary outcomes include modified ONLS and 10mWT through month 15; estimated primary completion April 2024. (NCT04762758 chunk 1)

MAXO suggestions: combination pharmacotherapy (MAXO:0000058 drug therapy), gait rehabilitation adjunct (MAXO:0000011 physical therapy), functional outcome assessment (MAXO:0000745 clinical assessment).

(B) PMP22 lowering (gene silencing / RNA therapeutics; preclinical)

A 2023 review summarizes multiple preclinical approaches targeting PMP22 overexpression, including siRNA formulations, AAV-mediated silencing, and ASOs that reversed CMT1A features in rodent models (review-level summary with multiple cited studies). (okamoto2023thecurrentstate pages 16-17)

(C) Gene therapy (examples)

A 2023 gene-therapy advances review notes that proposed approaches include gene replacement/addition, silencing, modification, and editing, with targeting of Schwann cells and/or neurons depending on subtype. (dong2024currenttreatmentmethods pages 2-4)

Example clinical gene-therapy trial: - scAAV1.tMCK.NTF3 for CMT1A (NCT03520751): Phase I/IIa trial record describes AAV1-based NTF3 delivery with detailed eligibility and immune-exclusion criteria (AAV1 antibody titers). Enrollment/status/endpoints were not available from the extracted chunk. (NCT03520751 chunk 2)

(D) HGF plasmid therapy (VM202 / Engensis)

ClinicalTrials.gov record NCT05361031 evaluates Engensis (VM202) in genetically confirmed CMT1A, with outcomes including change in nerve conduction velocity and HGF antibody generation over ~270 days; eligibility includes mild-to-moderate disease by CMTNS v2. (NCT05361031 chunk 2)

(E) Cell therapy (mesenchymal stromal cells)

ClinicalTrials.gov record NCT06328712 (Phase 1b) evaluates EN001 (allogeneic Wharton’s jelly-derived MSCs) in CMT1A, completed with n=6, with primary safety endpoints (DLTs) and multiple secondary exploratory efficacy outcomes including CMTNSv2, CMTES, electrophysiology, MRI, and SF‑36. (NCT06328712 chunk 1)

13. Prevention

Primary prevention of genetic CMT is not generally applicable in the classical public-health sense; preventive strategy is largely: - Genetic counseling and cascade testing (not directly evidenced in retrieved sources). - Avoidance of exposures/medications that could worsen neuropathy, suggested indirectly by trial exclusion criteria for “neurotoxic drugs” in the PXT3003 extension protocol. (NCT03023540 chunk 2)

14. Other Species / Natural Disease

The retrieved evidence set did not include a structured discussion of naturally occurring CMT analogs in companion animals (OMIA/VetCompass).

15. Model Organisms

The retrieved evidence emphasizes that treatment development has been tested largely in in vitro and rodent models, with discussion that larger-animal models may help translate dosing/safety. (dong2024currenttreatmentmethods pages 2-4)

A 2024 CMT1B-focused review highlights diverse model systems used for inherited neuropathies, including iPSC-derived organoids and multiple mouse models relevant to myelin disorders and proteostasis pathways. (mcculloch2024navigatingthelandscape pages 22-23)

Consolidated Evidence Tables

Topic Key data points (numbers) Source (first author year, journal) URL/DOI
Core disease definition and classification Charcot-Marie-Tooth disease (CMT) is one of the most common inherited peripheral neuropathies; genetically heterogeneous with >130 disease-causing genes reported. In a 1,515-patient specialist cohort, subtype distribution was CMT1 41.0% (621/1515), CMT2 19.4% (294/1515), intermediate CMT 13.5% (205/1515), HMN 9.2% (139/1515), HSN 6.1% (93/1515), sensory ataxic neuropathy 2.5% (38/1515), HNPP 4.8% (72/1515), complex neuropathy 3.5% (53/1515). Estimated prevalence reported as 1 in 2,500 to 1 in 10,000; another review gives 10–40 per 100,000. (record2024wholegenomesequencing pages 1-2, okamoto2023thecurrentstate pages 1-2) Record 2024, Brain; Okamoto 2023, Genes https://doi.org/10.1093/brain/awae064; https://doi.org/10.3390/genes14071391
Most common genetic causes in contemporary cohort Among solved cases (n=1165), most common diagnoses were PMP22 duplication/CMT1A 43.3% (505/1165), GJB1/CMTX1 13.0% (151/1165), PMP22 deletion/HNPP 6.2% (72/1165), MFN2/CMT2A 3.9% (46/1165). In the full 1,515-case cohort, PMP22 duplication represented 33.3% overall (505/1515). (record2024wholegenomesequencing pages 1-2, record2024wholegenomesequencing pages 2-3) Record 2024, Brain https://doi.org/10.1093/brain/awae064
Most common genetic causes in review cohorts Review summary of earlier cohorts: CMT1A/PMP22 55%, CMTX1/GJB1 15.2%, HNPP 9.2%, CMT1B/MPZ 8.5%, CMT2A/MFN2 4%. In a large commercial-lab cohort, genetic anomalies were found in 18.5% (3312/17,880); among positives: PMP22 duplications 56.7%, PMP22 deletions 21.9%, GJB1 6.7%, MPZ 5.3%, MFN2 4.3%; 94.9% of positives were in PMP22/GJB1/MPZ/MFN2. (okamoto2023thecurrentstate pages 1-2) Okamoto 2023, Genes https://doi.org/10.3390/genes14071391
Diagnostic yield: MLPA first-tier CNV testing In suspected CMT (n=64), MLPA diagnosed 25/64 (39%); specifically 14 PMP22 duplications and 11 PMP22 deletions. MLPA remains the preferred test for common PMP22 CNVs causing CMT1A/HNPP. (ceylan2023highdiagnosticyield pages 1-2, ceylan2023highdiagnosticyield pages 2-4, record2024wholegenomesequencing pages 2-3) Ceylan 2023, Rev Assoc Med Bras; Record 2024, Brain https://doi.org/10.1590/1806-9282.20220929; https://doi.org/10.1093/brain/awae064
Diagnostic yield: targeted NGS panels After negative PMP22 MLPA, 50 patients underwent targeted NGS; panel diagnostic yield was 36% (18/50) for pathogenic/likely pathogenic variants. Authors recommend algorithmic testing guided by phenotype, pedigree, and inheritance pattern. (ceylan2023highdiagnosticyield pages 1-2, ceylan2023highdiagnosticyield pages 2-4) Ceylan 2023, Rev Assoc Med Bras https://doi.org/10.1590/1806-9282.20220929
Diagnostic yield: WES In the same algorithmic series, WES diagnosed 4/5 (80%) panel-negative cases, with higher yield in the childhood group. (ceylan2023highdiagnosticyield pages 1-2) Ceylan 2023, Rev Assoc Med Bras https://doi.org/10.1590/1806-9282.20220929
Diagnostic yield: contemporary overall genetics and WGS uplift Single-center specialist cohort overall molecular diagnosis: 76.9% (1165/1515); highest in CMT1 96.8%, intermediate CMT 81.0%, HSN 69.9%; <50% in CMT2/HMN/complex neuropathies. In UK 100,000 Genomes Project cases (n=233), reported WGS diagnoses were 31.8% (74/233), but true WGS diagnostic rate after excluding otherwise-diagnosed cases was 19.7% (46/233). Overall WGS diagnostic uplift for the full cohort was 3.5%. (record2024wholegenomesequencing pages 1-2, record2024wholegenomesequencing pages 2-3) Record 2024, Brain https://doi.org/10.1093/brain/awae064
Outcome measure: CMT-FOM cohort and structure Multicenter validation in adult CMT1A: n=214, age 18–75 years, 58% female; recruited from US 130, UK 52, Italy 32. Final instrument is a 12-item disease-specific measure covering strength, upper/lower limb function, balance, and mobility; transformed to a 0–100 interval scale (0 = unaffected; 100 = severely affected). Mean score 47.7 ± 10.2, range 17–83. (mandarakas2024multicentervalidationof pages 1-2, mandarakas2024multicentervalidationof pages 5-6, mandarakas2024multicentervalidationof pages 6-9) Mandarakas 2024, Neurology https://doi.org/10.1212/wnl.0000000000207963
Outcome measure: CMT-FOM psychometrics Good Rasch model fit (χ² probability 0.15), internal consistency PSI 0.82, no floor/ceiling effects, excellent inter-rater reliability ICC 0.992 (95% CI 0.979–0.998). Convergent validity: correlation with CMTES-R r=0.643, p<0.001 and ONLS r=0.516, p<0.001; also correlated with gait assessment (r=0.65, p<0.001). Initial 13-item version showed Cronbach α=0.84 before Rasch refinement to 12 items. (mandarakas2024multicentervalidationof pages 1-2, mandarakas2024multicentervalidationof pages 3-5, mandarakas2024multicentervalidationof pages 6-9) Mandarakas 2024, Neurology https://doi.org/10.1212/wnl.0000000000207963
Other validated/used outcome measures in CMT trials Established measures referenced for CMT include CMTNSv1, CMTNSv2, Rasch-modified CMTNSv2/CMTES-R, and ONLS. Review notes limited sensitivity of older CMTNS versions and increasing use of Rasch-modified scales and biomarkers. (okamoto2023thecurrentstate pages 12-14, mandarakas2024multicentervalidationof pages 2-3) Okamoto 2023, Genes; Mandarakas 2024, Neurology https://doi.org/10.3390/genes14071391; https://doi.org/10.1212/wnl.0000000000207963

Table: This table condenses high-yield facts on Charcot-Marie-Tooth disease classification, major causal genes, diagnostic yields across testing modalities, and validated outcome-measure psychometrics. It is useful as a quick reference for disease knowledge base curation and evidence-backed clinical context.

Recent Developments (2023–2024 highlights)

  1. Whole-genome sequencing in routine care: WGS implementation (e.g., via UK NHS/100KGP) provides incremental diagnostic uplift and highlights the value of access to raw WGS for unsolved cases; large single-center yield reached 76.9% overall. (record2024wholegenomesequencing pages 1-2)
  2. Outcome measures readiness: The CMT-FOM was multicenter-validated in 2024 to support upcoming CMT1A trials, with strong reliability and validity metrics. (mandarakas2024multicentervalidationof pages 1-2, mandarakas2024multicentervalidationof pages 6-9)
  3. Late-stage pharmacologic development: Multiple Phase III trials of PXT3003 continue to use functional endpoints (mONLS, 10mWT) and longer follow-up windows consistent with slow progression. (NCT04762758 chunk 1, NCT02579759 chunk 1)
  4. Therapeutic modality expansion: Reviews in 2023–2024 emphasize gene therapy and gene silencing as a major direction (PMP22 silencing; AAV-based strategies), with translation challenges remaining. (okamoto2023thecurrentstate pages 16-17, dong2024currenttreatmentmethods pages 2-4)

URLs and publication dates (from evidence)

  • Record et al., Brain (advance access Mar 2024): https://doi.org/10.1093/brain/awae064 (record2024wholegenomesequencing pages 1-2)
  • Mandarakas et al., Neurology (Feb 2024): https://doi.org/10.1212/wnl.0000000000207963 (mandarakas2024multicentervalidationof pages 1-2)
  • Okamoto & Takashima, Genes (Jul 2023): https://doi.org/10.3390/genes14071391 (okamoto2023thecurrentstate pages 1-2)
  • Ceylan et al., Rev Assoc Med Bras (Feb 2023): https://doi.org/10.1590/1806-9282.20220929 (ceylan2023highdiagnosticyield pages 1-2)
  • ClinicalTrials.gov: PREMIER NCT04762758 (posted/maintained by sponsor; started 2021-03-30 per record): https://clinicaltrials.gov/study/NCT04762758 (NCT04762758 chunk 1)
  • ClinicalTrials.gov: PLEO-CMT NCT02579759: https://clinicaltrials.gov/study/NCT02579759 (NCT02579759 chunk 1)
  • ClinicalTrials.gov: EN001 NCT06328712: https://clinicaltrials.gov/study/NCT06328712 (NCT06328712 chunk 1)
  • ClinicalTrials.gov: VM202/Engensis NCT05361031: https://clinicaltrials.gov/study/NCT05361031 (NCT05361031 chunk 2)

Appendix: Suggested ontology terms (to be validated)

  • Disease: CMT (MONDO/OMIM/Orphanet identifiers not retrieved in this run)
  • HPO: distal muscle weakness; pes cavus; areflexia; gross motor delay (CMT4J); respiratory deficits (CMT4J) (mandarakas2024multicentervalidationof pages 5-6)
  • GO: myelination; axon maintenance; unfolded protein response
  • CL: Schwann cell
  • UBERON: peripheral nerve
  • MAXO: drug therapy; gene therapy; physical therapy; orthopedic surgery; assistive orthoses (supportive care not directly enumerated in the extracted sources but consistent with review framing)

References

  1. (record2024wholegenomesequencing pages 1-2): Christopher J Record, Menelaos Pipis, Mariola Skorupinska, Julian Blake, Roy Poh, James M Polke, Kelly Eggleton, Tina Nanji, Stephan Zuchner, Andrea Cortese, Henry Houlden, Alexander M Rossor, Matilde Laura, and Mary M Reilly. Whole genome sequencing increases the diagnostic rate in charcot-marie-tooth disease. Brain, 147:3144-3156, Mar 2024. URL: https://doi.org/10.1093/brain/awae064, doi:10.1093/brain/awae064. This article has 49 citations and is from a highest quality peer-reviewed journal.

  2. (okamoto2023thecurrentstate pages 1-2): Yuji Okamoto and Hiroshi Takashima. The current state of charcot–marie–tooth disease treatment. Genes, 14:1391, Jul 2023. URL: https://doi.org/10.3390/genes14071391, doi:10.3390/genes14071391. This article has 58 citations.

  3. (mandarakas2024multicentervalidationof pages 1-2): Melissa R. Mandarakas, Katy J. Eichinger, Paula Bray, Kayla M.D. Cornett, Michael E. Shy, Mary M. Reilly, Gita M. Ramdharry, Steven S. Scherer, Davide Pareyson, Timothy Estilow, Marnee J. McKay, David N. Herrmann, and Joshua Burns. Multicenter validation of the charcot-marie-tooth functional outcome measure. Neurology, Feb 2024. URL: https://doi.org/10.1212/wnl.0000000000207963, doi:10.1212/wnl.0000000000207963. This article has 12 citations and is from a highest quality peer-reviewed journal.

  4. (NCT04762758 chunk 1): Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients. Pharnext S.C.A.. 2021. ClinicalTrials.gov Identifier: NCT04762758

  5. (NCT06328712 chunk 1): Evaluate the Safety and Efficacy of EN001 in Patients With Charcot-Marie-Tooth Disease Type 1A. ENCell. 2024. ClinicalTrials.gov Identifier: NCT06328712

  6. (NCT02579759 chunk 1): Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients (PLEO-CMT). Pharnext S.C.A.. 2015. ClinicalTrials.gov Identifier: NCT02579759

  7. (NCT05361031 chunk 2): The Safety and Tolerability of Engensis (VM202) in Patients With Charcot-Marie-Tooth Disease Subtype 1A (CMT1A). Helixmith Co., Ltd.. 2020. ClinicalTrials.gov Identifier: NCT05361031

  8. (NCT03023540 chunk 2): Assessing Long Term Safety and Tolerability of PXT3003 in Patients With Charcot-Marie-Tooth Disease Type 1A. Pharnext S.C.A.. 2017. ClinicalTrials.gov Identifier: NCT03023540

  9. (ceylan2023highdiagnosticyield pages 1-2): Gülay Güleç Ceylan, Esra Habiloğlu, Büşranur Çavdarlı, Ebru Tuncez, Sule Bilen, Özlem Yayıcı Köken, and C. Nur Semerci Gündüz. High diagnostic yield with algorithmic molecular approach on hereditary neuropathies. Revista da Associação Médica Brasileira, 69:233-239, Feb 2023. URL: https://doi.org/10.1590/1806-9282.20220929, doi:10.1590/1806-9282.20220929. This article has 5 citations.

  10. (mandarakas2024multicentervalidationof pages 5-6): Melissa R. Mandarakas, Katy J. Eichinger, Paula Bray, Kayla M.D. Cornett, Michael E. Shy, Mary M. Reilly, Gita M. Ramdharry, Steven S. Scherer, Davide Pareyson, Timothy Estilow, Marnee J. McKay, David N. Herrmann, and Joshua Burns. Multicenter validation of the charcot-marie-tooth functional outcome measure. Neurology, Feb 2024. URL: https://doi.org/10.1212/wnl.0000000000207963, doi:10.1212/wnl.0000000000207963. This article has 12 citations and is from a highest quality peer-reviewed journal.

  11. (ceylan2023highdiagnosticyield pages 2-4): Gülay Güleç Ceylan, Esra Habiloğlu, Büşranur Çavdarlı, Ebru Tuncez, Sule Bilen, Özlem Yayıcı Köken, and C. Nur Semerci Gündüz. High diagnostic yield with algorithmic molecular approach on hereditary neuropathies. Revista da Associação Médica Brasileira, 69:233-239, Feb 2023. URL: https://doi.org/10.1590/1806-9282.20220929, doi:10.1590/1806-9282.20220929. This article has 5 citations.

  12. (record2024wholegenomesequencing pages 2-3): Christopher J Record, Menelaos Pipis, Mariola Skorupinska, Julian Blake, Roy Poh, James M Polke, Kelly Eggleton, Tina Nanji, Stephan Zuchner, Andrea Cortese, Henry Houlden, Alexander M Rossor, Matilde Laura, and Mary M Reilly. Whole genome sequencing increases the diagnostic rate in charcot-marie-tooth disease. Brain, 147:3144-3156, Mar 2024. URL: https://doi.org/10.1093/brain/awae064, doi:10.1093/brain/awae064. This article has 49 citations and is from a highest quality peer-reviewed journal.

  13. (okamoto2023thecurrentstate pages 16-17): Yuji Okamoto and Hiroshi Takashima. The current state of charcot–marie–tooth disease treatment. Genes, 14:1391, Jul 2023. URL: https://doi.org/10.3390/genes14071391, doi:10.3390/genes14071391. This article has 58 citations.

  14. (mcculloch2024navigatingthelandscape pages 22-23): Mary Kate McCulloch, Fatemeh Mehryab, and Afrooz Rashnonejad. Navigating the landscape of cmt1b: understanding genetic pathways, disease models, and potential therapeutic approaches. International Journal of Molecular Sciences, 25:9227, Aug 2024. URL: https://doi.org/10.3390/ijms25179227, doi:10.3390/ijms25179227. This article has 9 citations.

  15. (yalcouye2023geneticsofhearing pages 163-166): A Yalcouye. Genetics of hearing impairment and peripheral neuropathy in mali. Unknown journal, 2023.

  16. (okamoto2023thecurrentstate pages 12-14): Yuji Okamoto and Hiroshi Takashima. The current state of charcot–marie–tooth disease treatment. Genes, 14:1391, Jul 2023. URL: https://doi.org/10.3390/genes14071391, doi:10.3390/genes14071391. This article has 58 citations.

  17. (mandarakas2024multicentervalidationof pages 6-9): Melissa R. Mandarakas, Katy J. Eichinger, Paula Bray, Kayla M.D. Cornett, Michael E. Shy, Mary M. Reilly, Gita M. Ramdharry, Steven S. Scherer, Davide Pareyson, Timothy Estilow, Marnee J. McKay, David N. Herrmann, and Joshua Burns. Multicenter validation of the charcot-marie-tooth functional outcome measure. Neurology, Feb 2024. URL: https://doi.org/10.1212/wnl.0000000000207963, doi:10.1212/wnl.0000000000207963. This article has 12 citations and is from a highest quality peer-reviewed journal.

  18. (dong2024currenttreatmentmethods pages 2-4): Hongxian Dong, Boquan Qin, Hui Zhang, Lei Lei, and Shizhou Wu. Current treatment methods for charcot–marie–tooth diseases. Biomolecules, 14:1138, Sep 2024. URL: https://doi.org/10.3390/biom14091138, doi:10.3390/biom14091138. This article has 10 citations.

  19. (NCT03520751 chunk 2): Zarife Sahenk. Phase I/IIa Trial of scAAV1.tMCK.NTF3 for Treatment of CMT1A. Nationwide Children's Hospital. 2027. ClinicalTrials.gov Identifier: NCT03520751

  20. (mandarakas2024multicentervalidationof pages 3-5): Melissa R. Mandarakas, Katy J. Eichinger, Paula Bray, Kayla M.D. Cornett, Michael E. Shy, Mary M. Reilly, Gita M. Ramdharry, Steven S. Scherer, Davide Pareyson, Timothy Estilow, Marnee J. McKay, David N. Herrmann, and Joshua Burns. Multicenter validation of the charcot-marie-tooth functional outcome measure. Neurology, Feb 2024. URL: https://doi.org/10.1212/wnl.0000000000207963, doi:10.1212/wnl.0000000000207963. This article has 12 citations and is from a highest quality peer-reviewed journal.

  21. (mandarakas2024multicentervalidationof pages 2-3): Melissa R. Mandarakas, Katy J. Eichinger, Paula Bray, Kayla M.D. Cornett, Michael E. Shy, Mary M. Reilly, Gita M. Ramdharry, Steven S. Scherer, Davide Pareyson, Timothy Estilow, Marnee J. McKay, David N. Herrmann, and Joshua Burns. Multicenter validation of the charcot-marie-tooth functional outcome measure. Neurology, Feb 2024. URL: https://doi.org/10.1212/wnl.0000000000207963, doi:10.1212/wnl.0000000000207963. This article has 12 citations and is from a highest quality peer-reviewed journal.