Charcot-Marie-Tooth disease type 2E

disease

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Also known as autosomal dominant Charcot-Marie-Tooth disease type 2ECharcot Marie Tooth disease type 2ECharcot-Marie-Tooth disease type 2 caused by mutation in NEFLCharcot-Marie-Tooth disease, axonal, type 2ECharcot-Marie-Tooth disease, type 2ECMT 2ECMT2ENEFL Charcot-Marie-Tooth disease type 2

Summary

Charcot-Marie-Tooth disease type 2E (MONDO:0011894) is a disease with 4 cohort genes and 1 clinical trial.

At a glance

Prevalence: Unknown (Worldwide) [Orphanet-validated]
Cohort genes: 4
ClinVar variants: 523
Phenotypes (HPO): 24
Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

24 HPO clinical features (Orphanet curated; top 24 by frequency):

HPO ID	Term	Frequency
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0001760	Abnormal foot morphology	Very frequent (80-99%)
HP:0003477	Peripheral axonal neuropathy	Very frequent (80-99%)
HP:0003484	Upper limb muscle weakness	Very frequent (80-99%)
HP:0007141	Sensorimotor neuropathy	Very frequent (80-99%)
HP:0007220	Demyelinating motor neuropathy	Very frequent (80-99%)
HP:0007340	Lower limb muscle weakness	Very frequent (80-99%)
HP:0011402	Demyelinating sensory neuropathy	Very frequent (80-99%)
HP:0001265	Hyporeflexia	Frequent (30-79%)
HP:0001761	Pes cavus	Frequent (30-79%)
HP:0001884	Talipes calcaneovalgus	Frequent (30-79%)
HP:0002460	Distal muscle weakness	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003474	Somatic sensory dysfunction	Frequent (30-79%)
HP:0003693	Distal amyotrophy	Frequent (30-79%)
HP:0003701	Proximal muscle weakness	Frequent (30-79%)
HP:0009046	Difficulty running	Frequent (30-79%)
HP:0012896	Abnormal motor evoked potentials	Frequent (30-79%)
HP:0030235	Extremely elevated creatine kinase	Frequent (30-79%)
HP:0200101	Decreased/absent ankle reflexes	Frequent (30-79%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0002540	Inability to walk	Occasional (5-29%)
HP:0003376	Steppage gait	Occasional (5-29%)
HP:0000762	Decreased nerve conduction velocity	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease type 2E
Mondo ID	MONDO:0011894
MeSH	C537994
OMIM	607684
Orphanet	99939
DOID	DOID:0110165
ICD-11	1476045360
NCIT	C134953
SNOMED CT	717012004
UMLS	C1843225
MedGen	375127
GARD	0009193
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2E · Charcot Marie Tooth disease type 2E · Charcot-Marie-Tooth disease type 2 caused by mutation in NEFL · Charcot-Marie-Tooth disease, axonal, type 2E · Charcot-Marie-Tooth disease, type 2E · CMT 2E · CMT2E · NEFL Charcot-Marie-Tooth disease type 2

Data availability: 523 ClinVar variants · 1 GenCC gene-disease record · 3 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › Charcot-Marie-Tooth disease › Charcot-Marie-Tooth disease type 2 › Charcot-Marie-Tooth disease type 2E

Genetics & variants

GWAS landscape

No GWAS associations recorded — common-variant (GWAS) studies don’t cover this disease (typical for Mendelian / rare diseases). See the curated gene cohort and Mendelian overlap below.

Variant details and genetic-evidence tiers

ClinVar germline variants

523 retrieved; paginated sample, class counts are floors:

298 uncertain significance, 141 likely benign, 28 conflicting classifications of pathogenicity, 25 pathogenic, 16 benign/likely benign, 9 pathogenic/likely pathogenic, 3 likely pathogenic, 2 benign, 1 not provided

ClinVar	Variant (HGVS)	Gene	Classification	Review
2425516	NC_000008.10:g.(?24810323)(25892142_?)del	CDCA2	Pathogenic	criteria provided, single submitter
1074146	NM_006158.5(NEFL):c.1099C>T (p.Arg367Ter)	LOC126860330	Pathogenic	criteria provided, single submitter
2735143	NM_006158.5(NEFL):c.1150A>T (p.Ile384Phe)	LOC126860330	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
533513	NM_006158.5(NEFL):c.1117C>T (p.Gln373Ter)	LOC126860330	Pathogenic	criteria provided, single submitter
1215368	NM_006158.5(NEFL):c.417C>G (p.Tyr139Ter)	NEFL	Pathogenic	criteria provided, multiple submitters, no conflicts
14028	NM_006158.5(NEFL):c.995A>C (p.Gln332Pro)	NEFL	Pathogenic	criteria provided, single submitter
14029	NM_006158.5(NEFL):c.64C>T (p.Pro22Ser)	NEFL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14030	NM_006158.5(NEFL):c.22_23delinsAG (p.Pro8Arg)	NEFL	Pathogenic	no assertion criteria provided
14033	NM_006158.5(NEFL):c.281T>C (p.Leu94Pro)	NEFL	Pathogenic	no assertion criteria provided
1437655	NM_006158.5(NEFL):c.795C>G (p.Tyr265Ter)	NEFL	Pathogenic	criteria provided, single submitter
1685968	NM_006158.5(NEFL):c.506dup (p.Thr170fs)	NEFL	Pathogenic	criteria provided, single submitter
1685969	NM_006158.5(NEFL):c.54C>G (p.Tyr18Ter)	NEFL	Pathogenic	criteria provided, multiple submitters, no conflicts
192322	NM_006158.5(NEFL):c.1261C>T (p.Arg421Ter)	NEFL	Pathogenic	criteria provided, multiple submitters, no conflicts
1928219	NM_006158.5(NEFL):c.799_803del (p.Lys267fs)	NEFL	Pathogenic	criteria provided, single submitter
1973539	NM_006158.5(NEFL):c.832del (p.Glu278fs)	NEFL	Pathogenic	criteria provided, single submitter
1984363	NM_006158.4(NEFL):c.1414=	NEFL	Pathogenic	criteria provided, single submitter
2090590	NM_006158.5(NEFL):c.1272del (p.Ala423_Tyr424insTer)	NEFL	Pathogenic	criteria provided, single submitter
2838458	NM_006158.5(NEFL):c.1240dup (p.Gln414fs)	NEFL	Pathogenic	criteria provided, single submitter
3022773	NM_006158.5(NEFL):c.865_871del (p.Glu289fs)	NEFL	Pathogenic	criteria provided, single submitter
3639517	NM_006158.5(NEFL):c.171C>G (p.Tyr57Ter)	NEFL	Pathogenic	criteria provided, single submitter
3647897	NM_006158.5(NEFL):c.720C>G (p.Tyr240Ter)	NEFL	Pathogenic	criteria provided, single submitter
369981	NM_006158.5(NEFL):c.487G>T (p.Glu163Ter)	NEFL	Pathogenic	criteria provided, single submitter
3708693	NM_006158.5(NEFL):c.417C>A (p.Tyr139Ter)	NEFL	Pathogenic	criteria provided, single submitter
3720807	NM_006158.5(NEFL):c.556G>T (p.Glu186Ter)	NEFL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3730542	NM_006158.5(NEFL):c.223C>T (p.Gln75Ter)	NEFL	Pathogenic	criteria provided, single submitter
41236	NM_006158.5(NEFL):c.293A>G (p.Asn98Ser)	NEFL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
444742	NM_006158.5(NEFL):c.1195C>T (p.Arg399Ter)	NEFL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66671	NM_006158.5(NEFL):c.1186G>A (p.Glu396Lys)	NEFL	Pathogenic	criteria provided, multiple submitters, no conflicts
66688	NM_006158.5(NEFL):c.23C>G (p.Pro8Arg)	NEFL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
66689	NM_006158.5(NEFL):c.23C>T (p.Pro8Leu)	NEFL	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 9 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

GenCC gene–disease validity (cohort genes)

the Disease column is the GenCC-asserted condition — a cohort gene’s strongest validity may be for a related predisposition syndrome.

Gene	Classification	Inheritance	Disease	Records
NEFL	Definitive	Autosomal dominant	Charcot-Marie-Tooth disease	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NEFL	Orphanet:101085	Charcot-Marie-Tooth disease type 1F
NEFL	Orphanet:228374	Charcot-Marie-Tooth disease type 2B5
NEFL	Orphanet:99939	Autosomal dominant Charcot-Marie-Tooth disease type 2E
PMP22	Orphanet:101081	Charcot-Marie-Tooth disease type 1A
PMP22	Orphanet:3115	Roussy-Lévy syndrome
PMP22	Orphanet:640	Hereditary neuropathy with liability to pressure palsies
PMP22	Orphanet:64748	Dejerine-Sottas syndrome
PMP22	Orphanet:90658	Charcot-Marie-Tooth disease type 1E
PMP22	Orphanet:98916	Acute inflammatory demyelinating polyradiculoneuropathy

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NEFL	HGNC:7739	ENSG00000277586	P07196	Neurofilament light polypeptide	gencc,clinvar
CDCA2	HGNC:14623	ENSG00000184661	Q69YH5	Cell division cycle-associated protein 2	clinvar
MIR6841	HGNC:50070	ENSG00000283327		microRNA 6841	clinvar
PMP22	HGNC:9118	ENSG00000109099	Q01453	Peripheral myelin protein 22	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NEFL	Neurofilament light polypeptide	Neurofilaments usually contain three intermediate filament proteins: NEFL, NEFM, and NEFH which are involved in the maintenance of neuronal caliber.
CDCA2	Cell division cycle-associated protein 2	Regulator of chromosome structure during mitosis required for condensin-depleted chromosomes to retain their compact architecture through anaphase.
PMP22	Peripheral myelin protein 22	Might be involved in growth regulation, and in myelinization in the peripheral nervous system.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.0

Family distribution

Cohort families vs a genome-wide background (hypergeometric, BH-FDR; fold = observed/expected). Counts kept; sorted by enrichment, so the catch-all Other/Unknown bucket no longer leads.

Family	Genes	Fold	FDR
Other/Unknown	4	1.8×	0.097

Per-gene assignment

Symbol	Family	Druggable?	InterPro (top 3)
NEFL	Other/Unknown	no	Intermed_filament_DNA-bd, IF_conserved, IF_rod_dom
CDCA2	Other/Unknown	no	PP1-bd
MIR6841	Other/Unknown	no
PMP22	Other/Unknown	no	PMP22, PMP22/EMP/MP20/Claudin, PMP22_EMP_MP20

Expression context

Cohort genes with no expression data: 0.

3 cohort genes are a single-cell marker in ≥1 SCXA experiment.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
dorsal root ganglion	2
lateral nuclear group of thalamus	1
pons	1
oocyte	1
primordial germ cell in gonad	1
secondary oocyte	1
C1 segment of cervical spinal cord	1
blood	1
lower esophagus muscularis layer	1
olfactory bulb	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NEFL	214	broad	marker	dorsal root ganglion, pons, lateral nuclear group of thalamus
CDCA2	166	ubiquitous	marker	secondary oocyte, oocyte, primordial germ cell in gonad
MIR6841	32		yes	blood, C1 segment of cervical spinal cord, lower esophagus muscularis layer
PMP22	294	ubiquitous	marker	olfactory bulb, trigeminal ganglion, dorsal root ganglion

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NEFL	4,644
CDCA2	1,452
PMP22	647
MIR6841	0

Intra-cohort edges

A	B	Sources
NEFL	PMP22	string_interaction

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CDCA2	Q69YH5	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PMP22	Q01453	89.87
NEFL	P07196	73.66

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 4 evidence-associated genes (2 with Reactome annotation).

Pathways by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Ras activation upon Ca2+ influx through NMDA receptor	1	285.5×	0.007	NEFL
Unblocking of NMDA receptors, glutamate binding and activation	1	271.9×	0.007	NEFL
Negative regulation of NMDA receptor-mediated neuronal transmission	1	271.9×	0.007	NEFL
Long-term potentiation	1	237.9×	0.007	NEFL
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	184.2×	0.008	PMP22
Assembly and cell surface presentation of NMDA receptors	1	126.9×	0.009	NEFL
RAF/MAP kinase cascade	1	30.5×	0.032	NEFL

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intermediate filament polymerization or depolymerization	1	5617.3×	0.005	NEFL
response to sodium arsenite	1	2808.7×	0.005	NEFL
response to acrylamide	1	2808.7×	0.005	NEFL
neurofilament bundle assembly	1	1872.4×	0.005	NEFL
regulation of axon diameter	1	1123.5×	0.006	NEFL
peripheral nervous system axon regeneration	1	702.2×	0.006	NEFL
myelin assembly	1	624.1×	0.006	PMP22
neurofilament cytoskeleton organization	1	561.7×	0.006	NEFL
retrograde axonal transport	1	510.7×	0.006	NEFL
bleb assembly	1	510.7×	0.006	PMP22
locomotion	1	510.7×	0.006	NEFL
negative regulation of motor neuron apoptotic process	1	510.7×	0.006	NEFL
axonal transport of mitochondrion	1	468.1×	0.006	NEFL
response to corticosterone	1	374.5×	0.007	NEFL
motor neuron apoptotic process	1	374.5×	0.007	NEFL
protein polymerization	1	330.4×	0.007	NEFL
regulation of synapse maturation	1	312.1×	0.007	NEFL
postsynaptic modulation of chemical synaptic transmission	1	224.7×	0.009	NEFL
regulation of mitotic nuclear division	1	208.1×	0.009	CDCA2
peripheral nervous system development	1	193.7×	0.009	PMP22
anterograde axonal transport	1	193.7×	0.009	NEFL
positive regulation of axonogenesis	1	193.7×	0.009	NEFL
spinal cord development	1	170.2×	0.010	NEFL
response to peptide hormone	1	130.6×	0.012	NEFL
neuromuscular process controlling balance	1	110.1×	0.014	NEFL
intermediate filament organization	1	80.2×	0.018	NEFL
negative regulation of neuron projection development	1	79.1×	0.018	PMP22
hippocampus development	1	77.0×	0.018	NEFL
response to toxic substance	1	70.2×	0.018	NEFL
cerebral cortex development	1	68.5×	0.018	NEFL

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 2 · Undrugged: 2

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
PMP22	PROGESTERONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
PMP22	213	4
CDCA2	1	2
NEFL	0	0
MIR6841	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
PROGESTERONE	4	PMP22
CLOTRIMAZOLE	4	PMP22
OXAPROZIN	4	PMP22
SALMETEROL XINAFOATE	4	PMP22
AMIODARONE HYDROCHLORIDE	4	PMP22
TRIHEXYPHENIDYL HYDROCHLORIDE	4	PMP22
AMOXAPINE	4	PMP22
RALOXIFENE HYDROCHLORIDE	4	PMP22
IDARUBICIN	4	PMP22
OXYBUTYNIN CHLORIDE	4	PMP22
PINACIDIL ANHYDROUS	4	PMP22
NICARDIPINE HYDROCHLORIDE	4	PMP22
PILOCARPINE HYDROCHLORIDE	4	PMP22
PROTRIPTYLINE HYDROCHLORIDE	4	PMP22
BENZTROPINE MESYLATE	4	PMP22
BUSPIRONE HYDROCHLORIDE	4	PMP22
DOBUTAMINE HYDROCHLORIDE	4	PMP22
PROMAZINE HYDROCHLORIDE	4	PMP22
DICYCLOMINE HYDROCHLORIDE	4	PMP22
GUANFACINE HYDROCHLORIDE	4	PMP22
HYDROCORTISONE SODIUM SUCCINATE	4	PMP22
BROMOCRIPTINE MESYLATE	4	PMP22
DIHYDROERGOTAMINE MESYLATE	4	PMP22
DOXAZOSIN MESYLATE	4	PMP22
CYCLOBENZAPRINE HYDROCHLORIDE	4	PMP22
DEXBROMPHENIRAMINE MALEATE	4	PMP22
CLOMIPRAMINE HYDROCHLORIDE	4	PMP22
CHLORMEZANONE	4	PMP22
PROMETHAZINE HYDROCHLORIDE	4	PMP22
CITALOPRAM HYDROBROMIDE	4	PMP22

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

Cohort genes with ChEMBL bioactivity (full, sorted by assay count)

Symbol	Assays	Type breakdown
CDCA2	6	Binding:6
PMP22	1	Functional:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

30 approved/phased compounds have measured bioactivity against a cohort gene (and aren’t yet in disease-level trials). This is a research / tractability signal, NOT a therapeutic recommendation — a bioactivity row often reflects off-target or screening binding (e.g. promiscuous kinase inhibitors against a cohort kinase), implying no disease mechanism.

Compound	Max phase	Cohort target (bioactivity)
PROGESTERONE	4	PMP22
CLOTRIMAZOLE	4	PMP22
OXAPROZIN	4	PMP22
SALMETEROL XINAFOATE	4	PMP22
AMIODARONE HYDROCHLORIDE	4	PMP22
TRIHEXYPHENIDYL HYDROCHLORIDE	4	PMP22
AMOXAPINE	4	PMP22
RALOXIFENE HYDROCHLORIDE	4	PMP22
IDARUBICIN	4	PMP22
OXYBUTYNIN CHLORIDE	4	PMP22
PINACIDIL ANHYDROUS	4	PMP22
NICARDIPINE HYDROCHLORIDE	4	PMP22
PILOCARPINE HYDROCHLORIDE	4	PMP22
PROTRIPTYLINE HYDROCHLORIDE	4	PMP22
BENZTROPINE MESYLATE	4	PMP22
BUSPIRONE HYDROCHLORIDE	4	PMP22
DOBUTAMINE HYDROCHLORIDE	4	PMP22
PROMAZINE HYDROCHLORIDE	4	PMP22
DICYCLOMINE HYDROCHLORIDE	4	PMP22
GUANFACINE HYDROCHLORIDE	4	PMP22
HYDROCORTISONE SODIUM SUCCINATE	4	PMP22
BROMOCRIPTINE MESYLATE	4	PMP22
DIHYDROERGOTAMINE MESYLATE	4	PMP22
DOXAZOSIN MESYLATE	4	PMP22
CYCLOBENZAPRINE HYDROCHLORIDE	4	PMP22
DEXBROMPHENIRAMINE MALEATE	4	PMP22
CLOMIPRAMINE HYDROCHLORIDE	4	PMP22
CHLORMEZANONE	4	PMP22
PROMETHAZINE HYDROCHLORIDE	4	PMP22
CITALOPRAM HYDROBROMIDE	4	PMP22

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	PMP22
B	Phased (≥1) drug, not yet approved	1	CDCA2
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	NEFL, MIR6841

Undrugged target profiles

2 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
NEFL	0	—
MIR6841	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT05902351	Not specified	RECRUITING	Natural History Study for Charcot Marie Tooth Disease

Cohort genes: NEFL, CDCA2, MIR6841, PMP22