Charcot-Marie-Tooth disease axonal type 2X

Summary

Charcot-Marie-Tooth disease axonal type 2X (MONDO:0014726) is a disease caused by SPG11 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SPG11 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 324

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		29	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease axonal type 2X
Mondo ID	MONDO:0014726
EFO	EFO:1001983
OMIM	616668
Orphanet	466775
DOID	DOID:0110176
UMLS	C5569024
MedGen	1800447
GARD	0017830
Is cancer (heuristic)	no

Also known as: ARCMT2X · autosomal recessive Charcot-Marie-Tooth disease type 2 due to SPG11 mutation · Charcot-Marie-Tooth disease caused by mutation in SPG11 · Charcot-Marie-Tooth disease, axonal, type 2x · CMT2X · SPG11 Charcot-Marie-Tooth disease

Data availability: 324 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 2X

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, Charcot-Marie-Tooth disease axonal type 2V, autosomal dominant Charcot-Marie-Tooth disease type 2W, 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

324 retrieved; paginated sample, class counts are floors:

131 uncertain significance, 44 conflicting classifications of pathogenicity, 38 pathogenic, 36 likely pathogenic, 35 pathogenic/likely pathogenic, 22 benign/likely benign, 11 likely benign, 7 benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
41315	NM_025137.4(SPG11):c.4307_4308del (p.Gln1436fs)	LOC130056973	Pathogenic	criteria provided, multiple submitters, no conflicts
1072015	NM_025137.4(SPG11):c.4432C>T (p.Gln1478Ter)	SPG11	Pathogenic	criteria provided, single submitter
1109	NM_025137.4(SPG11):c.6100C>T (p.Arg2034Ter)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1110	NM_025137.4(SPG11):c.529_533del (p.Ile177fs)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1111	NM_025137.4(SPG11):c.118C>T (p.Gln40Ter)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1112	NM_025137.4(SPG11):c.733_734del (p.Met245fs)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1116	NM_025137.4(SPG11):c.5623C>T (p.Gln1875Ter)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1117	NM_025137.4(SPG11):c.3075dup (p.Glu1026fs)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
1180842	NM_025137.4(SPG11):c.3687_3688insC (p.Ile1230fs)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1453973	NM_025137.4(SPG11):c.1090C>T (p.Gln364Ter)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1499692	NM_025137.4(SPG11):c.258-2A>C	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1780713	NM_025137.4(SPG11):c.1819_1822delinsAT (p.Ser607fs)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1805308	NM_025137.4(SPG11):c.6204A>G (p.Thr2068=)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2095237	NM_025137.4(SPG11):c.4339C>T (p.Gln1447Ter)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
218142	NM_025137.4(SPG11):c.6632dup (p.Pro2212fs)	SPG11	Pathogenic	criteria provided, single submitter
218143	NM_025137.4(SPG11):c.592C>T (p.Gln198Ter)	SPG11	Pathogenic	criteria provided, single submitter
235890	NM_025137.4(SPG11):c.6899T>C (p.Leu2300Pro)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
235891	NM_025137.4(SPG11):c.1621C>T (p.Gln541Ter)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
241590	NM_025137.4(SPG11):c.1348dup (p.Ile450fs)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
2736195	NM_025137.4(SPG11):c.3143_3144dup (p.Asp1049fs)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
2753714	NM_025137.4(SPG11):c.6971_6972dup (p.Ile2325fs)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2765321	NM_025137.4(SPG11):c.1326dup (p.Val443fs)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2780293	NM_025137.4(SPG11):c.5794del (p.His1932fs)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
2811100	NM_025137.4(SPG11):c.3175_3176delinsTG (p.Ala1059Ter)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
2841245	NM_025137.4(SPG11):c.5109_5115dup (p.Lys1706delinsGlyTyrTer)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
316101	NM_025137.4(SPG11):c.2317-13C>G	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3577135	NM_025137.4(SPG11):c.6859C>T (p.Gln2287Ter)	SPG11	Pathogenic	criteria provided, multiple submitters, no conflicts
3577141	NM_025137.4(SPG11):c.6271C>T (p.Gln2091Ter)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3577152	NM_025137.4(SPG11):c.4868del (p.Leu1623fs)	SPG11	Pathogenic	criteria provided, single submitter
3577154	NM_025137.4(SPG11):c.4492_4493del (p.Val1498fs)	SPG11	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 12 · Orphanet: 12 · 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
SPG11	Strong	Autosomal recessive	Charcot-Marie-Tooth disease axonal type 2X	12

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SPG11	Orphanet:2822	Autosomal recessive spastic paraplegia type 11
SPG11	Orphanet:300605	Juvenile amyotrophic lateral sclerosis
SPG11	Orphanet:466775	Autosomal recessive Charcot-Marie-Tooth disease type 2X
TRPV4	Orphanet:1216	Autosomal dominant congenital benign spinal muscular atrophy
TRPV4	Orphanet:263482	Spondyloepimetaphyseal dysplasia, Maroteaux type
TRPV4	Orphanet:2635	Metatropic dysplasia
TRPV4	Orphanet:431255	Scapuloperoneal spinal muscular atrophy
TRPV4	Orphanet:85169	Familial digital arthropathy-brachydactyly
TRPV4	Orphanet:86820	Familial avascular necrosis of femoral head
TRPV4	Orphanet:93304	Autosomal dominant brachyolmia
TRPV4	Orphanet:93314	Spondylometaphyseal dysplasia, Kozlowski type
TRPV4	Orphanet:99937	Autosomal dominant Charcot-Marie-Tooth disease type 2C

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
SPG11	HGNC:11226	ENSG00000104133	Q96JI7	Spatacsin	gencc,clinvar
TRPV4	HGNC:18083	ENSG00000111199	Q9HBA0	Transient receptor potential cation channel subfamily V member 4	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SPG11	Spatacsin	May play a role in neurite plasticity by maintaining cytoskeleton stability and regulating synaptic vesicle transport.
TRPV4	Transient receptor potential cation channel subfamily V member 4	Non-selective calcium permeant cation channel involved in osmotic sensitivity and mechanosensitivity.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Ion channel	1	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SPG11	Other/Unknown	no		Spatacsin, Spatacsin_C_dom
TRPV4	Ion channel	yes		Ankyrin_rpt, Ion_trans_dom, TrpV1-4

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
bronchial epithelial cell	1
calcaneal tendon	1
granulocyte	1
cartilage tissue	1
lower esophagus mucosa	1
olfactory segment of nasal mucosa	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SPG11	295	ubiquitous	marker	bronchial epithelial cell, granulocyte, calcaneal tendon
TRPV4	171	ubiquitous	marker	cartilage tissue, lower esophagus mucosa, olfactory segment of nasal mucosa

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
TRPV4	1,948
SPG11	1,691

Structural data

PDB: 2 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
TRPV4	Q9HBA0	19
SPG11	Q96JI7	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 2 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
TRP channels	1	407.9×	0.005	TRPV4
High laminar flow shear stress activates signaling by PIEZO1 and PECAM1:CDH5:KDR in endothelial cells	1	160.8×	0.006	TRPV4

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
hyperosmotic salinity response	1	8426.0×	0.002	TRPV4
phagosome-lysosome fusion involved in apoptotic cell clearance	1	8426.0×	0.002	SPG11
blood vessel endothelial cell delamination	1	8426.0×	0.002	TRPV4
vasopressin secretion	1	4213.0×	0.002	TRPV4
positive regulation of striated muscle contraction	1	4213.0×	0.002	TRPV4
regulation of response to osmotic stress	1	4213.0×	0.002	TRPV4
calcium ion import into cytosol	1	4213.0×	0.002	TRPV4
localization within membrane	1	2808.7×	0.002	SPG11
cellular hypotonic salinity response	1	2808.7×	0.002	TRPV4
positive regulation of macrophage inflammatory protein 1 alpha production	1	2808.7×	0.002	TRPV4
axo-dendritic transport	1	2106.5×	0.003	SPG11
positive regulation of microtubule depolymerization	1	1685.2×	0.003	TRPV4
autophagosome organization	1	1685.2×	0.003	SPG11
positive regulation of chemokine (C-C motif) ligand 5 production	1	1404.3×	0.003	TRPV4
walking behavior	1	1404.3×	0.003	SPG11
negative regulation of brown fat cell differentiation	1	1404.3×	0.003	TRPV4
positive regulation of chemokine (C-X-C motif) ligand 1 production	1	1404.3×	0.003	TRPV4
corticospinal tract morphogenesis	1	1203.7×	0.003	SPG11
cartilage development involved in endochondral bone morphogenesis	1	1203.7×	0.003	TRPV4
regulation of aerobic respiration	1	1053.2×	0.003	TRPV4
cortical microtubule organization	1	936.2×	0.003	TRPV4
multicellular organismal-level water homeostasis	1	842.6×	0.004	TRPV4
osmosensory signaling pathway	1	766.0×	0.004	TRPV4
diet induced thermogenesis	1	702.2×	0.004	TRPV4
cellular hypotonic response	1	702.2×	0.004	TRPV4
positive regulation of vascular permeability	1	648.1×	0.004	TRPV4
cellular response to osmotic stress	1	601.9×	0.004	TRPV4
positive regulation of monocyte chemotactic protein-1 production	1	601.9×	0.004	TRPV4
motor neuron apoptotic process	1	561.7×	0.004	SPG11
regulation of store-operated calcium entry	1	526.6×	0.004	SPG11

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 1 · 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
TRPV4	6	3
SPG11	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANNABINOL	3	TRPV4
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
ABT-102	1	TRPV4

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
TRPV4	99	Binding:94, Functional:5
SPG11	1	Binding:1

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

6 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)
CANNABINOL	3	TRPV4
TETRAHYDROCANNABIVARIN	2	TRPV4
CANNABIDIVARIN	2	TRPV4
GSK2798745	2	TRPV4
CANNABIGEROL	2	TRPV4
ABT-102	1	TRPV4

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	TRPV4
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SPG11

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)
SPG11	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.