Charcot-Marie-Tooth disease axonal type 2V

Summary

Charcot-Marie-Tooth disease axonal type 2V (MONDO:0014665) is a disease caused by NAGLU (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: NAGLU (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 1,191

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		21	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease axonal type 2V
Mondo ID	MONDO:0014665
OMIM	616491
Orphanet	447964
DOID	DOID:0110178
UMLS	C5569050
MedGen	1800473
GARD	0017777
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2 due to NAGLU mutation · autosomal dominant Charcot-Marie-Tooth disease type 2V · Charcot-Marie-Tooth disease caused by mutation in NAGLU · Charcot-Marie-Tooth disease, axonal, type 2V · CMT2V · hereditary adult-onset painful axonal polyneuropathy · NAGLU Charcot-Marie-Tooth disease

Data availability: 1,191 ClinVar variants · 3 GenCC gene-disease records.

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 axonal type 2V

Related subtypes (37): Charcot-Marie-Tooth disease type 2A1, Charcot-Marie-Tooth disease type 2B, Charcot-Marie-Tooth disease type 2D, Charcot-Marie-Tooth disease type 2B1, Charcot-Marie-Tooth disease type 2B2, Charcot-Marie-Tooth disease axonal type 2C, Charcot-Marie-Tooth disease axonal type 2F, Charcot-Marie-Tooth disease type 2I, Charcot-Marie-Tooth disease type 2E, Charcot-Marie-Tooth disease axonal type 2H, Charcot-Marie-Tooth disease type 2J, Charcot-Marie-Tooth disease axonal type 2K, Charcot-Marie-Tooth disease axonal type 2L, Charcot-Marie-Tooth disease type 2A2, giant axonal neuropathy 2, Charcot-Marie-Tooth disease axonal type 2N, Charcot-Marie-Tooth disease axonal type 2O, Charcot-Marie-Tooth disease axonal type 2P, Charcot-Marie-Tooth disease axonal type 2Q, Charcot-Marie-Tooth disease type 2R, Charcot-Marie-Tooth disease axonal type 2S, Charcot-Marie-Tooth disease axonal type 2U, autosomal dominant Charcot-Marie-Tooth disease type 2W, Charcot-Marie-Tooth disease axonal type 2X, Charcot-Marie-Tooth disease type 2Y, Charcot-Marie-Tooth disease axonal type 2Z, Charcot-Marie-Tooth disease axonal type 2CC, autosomal dominant Charcot-Marie-Tooth disease type 2M, Charcot-Marie-Tooth disease type 2B5, autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation, autosomal dominant Charcot-Marie-Tooth disease type 2 due to TFG mutation, autosomal dominant Charcot-Marie-Tooth disease type 2K, Charcot-Marie-Tooth disease, axonal, type 2EE, autosomal dominant charcot-marie-tooth disease type 2 due to DGAT2 mutation, Charcot-Marie-Tooth disease type 2T, MME-related autosomal dominant Charcot Marie Tooth disease type 2, Charcot-Marie-tooth disease, axonal, type 2DD

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

600 retrieved; paginated sample, class counts are floors:

305 likely benign, 192 uncertain significance, 48 pathogenic, 20 likely pathogenic, 17 pathogenic/likely pathogenic, 15 conflicting classifications of pathogenicity, 2 benign, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1066367	NM_000263.4(NAGLU):c.214_237dup (p.Ala72_Gly79dup)	LOC130060903	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068486	NM_000263.4(NAGLU):c.54_60dup (p.Ala21fs)	LOC130060903	Pathogenic	criteria provided, single submitter
1068957	NM_000263.4(NAGLU):c.222_223del (p.Val75fs)	LOC130060903	Pathogenic	criteria provided, single submitter
1071442	NM_000263.4(NAGLU):c.136del (p.Ala46fs)	LOC130060903	Pathogenic	criteria provided, single submitter
1076543	NM_000263.4(NAGLU):c.71_87del (p.Asp24fs)	LOC130060903	Pathogenic	criteria provided, single submitter
1382617	NM_000263.4(NAGLU):c.59dup (p.Ala21fs)	LOC130060903	Pathogenic	criteria provided, single submitter
1454105	NM_000263.4(NAGLU):c.252_265del (p.Ala86fs)	LOC130060903	Pathogenic	criteria provided, single submitter
1456865	NM_000263.4(NAGLU):c.222_247del (p.Val75fs)	LOC130060903	Pathogenic	criteria provided, multiple submitters, no conflicts
1458683	NM_000263.4(NAGLU):c.3G>A (p.Met1Ile)	LOC130060903	Pathogenic	criteria provided, single submitter
1459501	NM_000263.4(NAGLU):c.192del (p.Tyr65fs)	LOC130060903	Pathogenic	criteria provided, multiple submitters, no conflicts
1569	NM_000263.4(NAGLU):c.142T>C (p.Phe48Leu)	LOC130060903	Pathogenic	criteria provided, single submitter
1067431	NM_000263.4(NAGLU):c.457G>A (p.Glu153Lys)	NAGLU	Pathogenic	criteria provided, multiple submitters, no conflicts
1067432	NM_000263.4(NAGLU):c.1081T>C (p.Trp361Arg)	NAGLU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068849	NM_000263.4(NAGLU):c.1453dup (p.Val485fs)	NAGLU	Pathogenic	criteria provided, single submitter
1069834	NC_000017.10:g.(?40690347)(40690783_?)del	NAGLU	Pathogenic	criteria provided, single submitter
1070682	NM_000263.4(NAGLU):c.454C>T (p.Arg152Ter)	NAGLU	Pathogenic	criteria provided, single submitter
1071435	NM_000263.4(NAGLU):c.432G>A (p.Trp144Ter)	NAGLU	Pathogenic	criteria provided, multiple submitters, no conflicts
1075574	NM_000263.4(NAGLU):c.1162C>T (p.Gln388Ter)	NAGLU	Pathogenic	criteria provided, single submitter
1076452	NM_000263.4(NAGLU):c.603G>A (p.Trp201Ter)	NAGLU	Pathogenic	criteria provided, single submitter
1323323	NM_000263.4(NAGLU):c.2045T>G (p.Leu682Arg)	NAGLU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1343458	NM_000263.4(NAGLU):c.410_413del (p.Thr137fs)	NAGLU	Pathogenic	criteria provided, multiple submitters, no conflicts
1356379	NM_000263.4(NAGLU):c.640dup (p.Leu214fs)	NAGLU	Pathogenic	criteria provided, single submitter
1360395	NM_000263.4(NAGLU):c.1173dup (p.Thr392fs)	NAGLU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1362789	NM_000263.4(NAGLU):c.1460dup (p.His487fs)	NAGLU	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1376432	NM_000263.4(NAGLU):c.820del (p.Ser274fs)	NAGLU	Pathogenic	criteria provided, single submitter
1377108	NM_000263.4(NAGLU):c.1773del (p.Leu591_Leu592insTer)	NAGLU	Pathogenic	criteria provided, single submitter
1384177	NM_000263.4(NAGLU):c.713del (p.Met238fs)	NAGLU	Pathogenic	criteria provided, single submitter
1405883	NM_000263.4(NAGLU):c.387C>G (p.Tyr129Ter)	NAGLU	Pathogenic	criteria provided, single submitter
1409649	NM_000263.4(NAGLU):c.1570C>T (p.Gln524Ter)	NAGLU	Pathogenic	criteria provided, single submitter
1429252	NM_000263.4(NAGLU):c.441G>A (p.Trp147Ter)	NAGLU	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 3 · 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
NAGLU	Strong	Autosomal dominant	Charcot-Marie-Tooth disease axonal type 2V	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NAGLU	Orphanet:447964	Autosomal dominant Charcot-Marie-Tooth disease type 2V
NAGLU	Orphanet:79270	Sanfilippo syndrome type B
COASY	Orphanet:397725	COASY protein-associated neurodegeneration

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
NAGLU	HGNC:7632	ENSG00000108784	P54802	Alpha-N-acetylglucosaminidase	gencc,clinvar
COASY	HGNC:29932	ENSG00000068120	Q13057	Bifunctional coenzyme A synthase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NAGLU	Alpha-N-acetylglucosaminidase	Involved in the degradation of heparan sulfate.
COASY	Bifunctional coenzyme A synthase	Bifunctional enzyme that catalyzes the fourth step of the coenzyme A biosynthetic pathway, the adenylation of 4’-phosphopantetheine, and the fifth step, the phosphorylation of dephospho-CoA to CoA.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Kinase	1	13.9×	0.142
Enzyme (other)	1	6.0×	0.160

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NAGLU	Enzyme (other)	yes	3.2.1.50	NAGLU, GH_hydrolase_sf, NAGLU_N
COASY	Kinase	yes	2.7.1.24	Depp_CoAkinase, Cyt_trans-like, Rossmann-like_a/b/a_fold

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
body of pancreas	1
mucosa of stomach	1
stromal cell of endometrium	1
lower esophagus mucosa	1
mucosa of transverse colon	1
parotid gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NAGLU	268	ubiquitous	marker	stromal cell of endometrium, body of pancreas, mucosa of stomach
COASY	280	ubiquitous	marker	parotid gland, mucosa of transverse colon, lower esophagus mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COASY	3,273
NAGLU	1,200

Structural data

PDB: 1 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
NAGLU	P54802	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
COASY	Q13057	89.51

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 2 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
MPS IIIB - Sanfilippo syndrome B	1	5710.0×	0.002	NAGLU
Mucopolysaccharidoses	1	951.7×	0.005	NAGLU
Coenzyme A biosynthesis	1	713.8×	0.005	COASY
Diseases of carbohydrate metabolism	1	407.9×	0.007	NAGLU
Heparan sulfate/heparin (HS-GAG) metabolism	1	271.9×	0.007	NAGLU
HS-GAG degradation	1	248.3×	0.007	NAGLU
Glycosaminoglycan metabolism	1	109.8×	0.014	NAGLU
Metabolism of carbohydrates and carbohydrate derivatives	1	60.1×	0.023	NAGLU
Diseases of metabolism	1	40.2×	0.030	NAGLU
Disease	1	6.5×	0.162	NAGLU
Metabolism	1	5.8×	0.165	NAGLU

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
response to disaccharide	1	8426.0×	0.004	NAGLU
rod bipolar cell differentiation	1	4213.0×	0.004	NAGLU
ganglioside metabolic process	1	2106.5×	0.004	NAGLU
left ventricular cardiac muscle tissue morphogenesis	1	2106.5×	0.004	NAGLU
cone retinal bipolar cell differentiation	1	2106.5×	0.004	NAGLU
cytoplasm organization	1	1404.3×	0.004	NAGLU
heparin proteoglycan metabolic process	1	1404.3×	0.004	NAGLU
glycosaminoglycan metabolic process	1	1203.7×	0.004	NAGLU
inner ear receptor cell development	1	1203.7×	0.004	NAGLU
heparan sulfate proteoglycan catabolic process	1	936.2×	0.004	NAGLU
mitral valve morphogenesis	1	842.6×	0.004	NAGLU
retinal rod cell development	1	842.6×	0.004	NAGLU
microglia differentiation	1	766.0×	0.004	NAGLU
coenzyme A biosynthetic process	1	766.0×	0.004	COASY
cerebellar Purkinje cell layer development	1	766.0×	0.004	NAGLU
endothelium development	1	648.1×	0.005	NAGLU
amyloid precursor protein metabolic process	1	648.1×	0.005	NAGLU
collagen metabolic process	1	526.6×	0.005	NAGLU
locomotor rhythm	1	526.6×	0.005	NAGLU
superoxide metabolic process	1	495.6×	0.005	NAGLU
astrocyte activation	1	495.6×	0.005	NAGLU
obsolete vesicle tethering	1	495.6×	0.005	NAGLU
nerve development	1	468.1×	0.005	NAGLU
aorta morphogenesis	1	443.5×	0.005	NAGLU
hormone metabolic process	1	443.5×	0.005	NAGLU
middle ear morphogenesis	1	351.1×	0.005	NAGLU
exploration behavior	1	324.1×	0.006	NAGLU
microglial cell activation	1	312.1×	0.006	NAGLU
cardiac muscle cell development	1	312.1×	0.006	NAGLU
multicellular organismal-level iron ion homeostasis	1	290.6×	0.006	NAGLU

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 1

Druggability breadth: 2 of 2 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COASY	1	2
NAGLU	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	COASY

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
COASY	10	Binding:10
NAGLU	4	Binding:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
NAGLU	3.2.1.50	alpha-N-acetylglucosaminidase
COASY	2.7.1.24, 2.7.7.3	dephospho-CoA kinase, pantetheine-phosphate adenylyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

1 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)
MOLIBRESIB	2	COASY

Druggability pyramid

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

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

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
NAGLU	4	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.