Charcot-Marie-Tooth disease axonal type 2O

Summary

Charcot-Marie-Tooth disease axonal type 2O (MONDO:0013644) is a disease caused by DYNC1H1 (GenCC Strong), with 5 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Europe)
• Causal gene: DYNC1H1 (GenCC Strong)
• Cohort genes: 5
• ClinVar variants: 4,498
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	<1 / 1 000 000		Europe	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	Charcot-Marie-Tooth disease axonal type 2O
Mondo ID	MONDO:0013644
OMIM	614228
Orphanet	284232
DOID	DOID:0110175
UMLS	C3280220
MedGen	481850
GARD	0012434
Is cancer (heuristic)	no

Also known as: autosomal dominant Charcot-Marie-Tooth disease type 2O · Charcot-Marie-Tooth disease caused by mutation in DYNC1H1 · Charcot-Marie-Tooth disease type 2O · Charcot-Marie-Tooth disease, axonal, type 20 · Charcot-Marie-Tooth disease, axonal, type 2O · CMT2O · DYNC1H1 Charcot-Marie-Tooth disease

Data availability: 4,498 ClinVar variants · 2 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 2O

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 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 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:

261 uncertain significance, 233 likely benign, 69 conflicting classifications of pathogenicity, 21 benign, 8 benign/likely benign, 6 pathogenic/likely pathogenic, 1 pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1053168	NM_001376.5(DYNC1H1):c.5035C>T (p.Arg1679Trp)	DYNC1H1	Pathogenic	criteria provided, single submitter
1075692	NM_001376.5(DYNC1H1):c.1739A>C (p.Glu580Ala)	DYNC1H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1193236	NM_001376.5(DYNC1H1):c.10574G>A (p.Arg3525His)	DYNC1H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1298386	NM_001376.5(DYNC1H1):c.10016G>A (p.Arg3339His)	DYNC1H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1315552	NM_001376.5(DYNC1H1):c.751C>A (p.Arg251Ser)	DYNC1H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1359385	NM_001376.5(DYNC1H1):c.11015C>T (p.Ser3672Leu)	DYNC1H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
139652	NM_001376.5(DYNC1H1):c.1792C>T (p.Arg598Cys)	DYNC1H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334533	NM_001376.5(DYNC1H1):c.9547dup (p.Tyr3183fs)	DYNC1H1	Likely pathogenic	criteria provided, single submitter
1002297	NM_001376.5(DYNC1H1):c.5987C>G (p.Pro1996Arg)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002335	NM_001376.5(DYNC1H1):c.13265A>C (p.Lys4422Thr)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1002755	NM_001376.5(DYNC1H1):c.11774A>G (p.Gln3925Arg)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1005960	NM_001376.5(DYNC1H1):c.200A>G (p.Lys67Arg)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1018365	NM_001376.5(DYNC1H1):c.8177+6A>G	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1022063	NM_001376.5(DYNC1H1):c.13060G>T (p.Asp4354Tyr)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1033419	NM_001376.5(DYNC1H1):c.12514-5A>G	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1036574	NM_001376.5(DYNC1H1):c.12797A>G (p.Asn4266Ser)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1057796	NM_001376.5(DYNC1H1):c.11543G>A (p.Gly3848Asp)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1063675	NM_001376.5(DYNC1H1):c.11686G>A (p.Val3896Met)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1090984	NM_001376.5(DYNC1H1):c.4543-5A>C	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1126222	NM_001376.5(DYNC1H1):c.11472G>A (p.Leu3824=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1198839	NM_001376.5(DYNC1H1):c.2624C>T (p.Ser875Leu)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1200585	NM_001376.5(DYNC1H1):c.2441C>G (p.Ala814Gly)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1216665	NM_001376.5(DYNC1H1):c.8343+4C>T	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1216714	NM_001376.5(DYNC1H1):c.1103G>A (p.Arg368Gln)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1217636	NM_001376.5(DYNC1H1):c.2275C>T (p.Arg759Cys)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1219422	NM_001376.5(DYNC1H1):c.13546G>A (p.Val4516Met)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1256079	NM_001376.5(DYNC1H1):c.5049+8T>C	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128922	NM_001376.5(DYNC1H1):c.10656C>T (p.Tyr3552=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128923	NM_001376.5(DYNC1H1):c.12102+6G>A	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
128925	NM_001376.5(DYNC1H1):c.7224C>T (p.Ala2408=)	DYNC1H1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

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
DYNC1H1	Strong	Autosomal dominant	Charcot-Marie-Tooth disease axonal type 2O	9

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
DYNC1H1	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability
DYNC1H1	Orphanet:209341	DYNC1H1-related autosomal dominant childhood-onset proximal spinal muscular atrophy
DYNC1H1	Orphanet:284232	Autosomal dominant Charcot-Marie-Tooth disease type 2O
AMN	Orphanet:35858	Imerslund-Gräsbeck syndrome
ADSS1	Orphanet:482601	Adenylosuccinate synthetase-like 1-related distal myopathy
ABCD1	Orphanet:139396	X-linked cerebral adrenoleukodystrophy
ABCD1	Orphanet:139399	Adrenomyeloneuropathy
ABCD1	Orphanet:369942	CADDS
ABCD1	Orphanet:388	Hirschsprung disease

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	gencc,clinvar
AMN	HGNC:14604	ENSG00000166126	Q9BXJ7	Protein amnionless	clinvar
ADSS1	HGNC:20093	ENSG00000185100	Q8N142	Adenylosuccinate synthetase isozyme 1	clinvar
ABCD1	HGNC:61	ENSG00000101986	P33897	ATP-binding cassette sub-family D member 1	clinvar
JAG2	HGNC:6189	ENSG00000184916	Q9Y219	Protein jagged-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
DYNC1H1	Cytoplasmic dynein 1 heavy chain 1	Cytoplasmic dynein 1 acts as a motor for the intracellular retrograde motility of vesicles and organelles along microtubules.
AMN	Protein amnionless	Membrane-bound component of the endocytic receptor formed by AMN and CUBN.
ADSS1	Adenylosuccinate synthetase isozyme 1	Component of the purine nucleotide cycle (PNC), which interconverts IMP and AMP to regulate the nucleotide levels in various tissues, and which contributes to glycolysis and ammoniagenesis.
ABCD1	ATP-binding cassette sub-family D member 1	ATP-dependent transporter of the ATP-binding cassette (ABC) family involved in the transport of very long chain fatty acid (VLCFA)-CoA from the cytosol to the peroxisome lumen.
JAG2	Protein jagged-2	Putative Notch ligand involved in the mediation of Notch signaling.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 3 · Druggable fraction: 0.4

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
Transporter	1	15.6×	0.188
Enzyme (other)	1	2.4×	0.530
Other/Unknown	3	1.1×	0.608

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
AMN	Other/Unknown	no		AMN
ADSS1	Enzyme (other)	yes	6.3.4.4	Adenylosuccinate_synthetase, Adenylosuccin_syn_GTP-bd, P-loop_NTPase
ABCD1	Transporter	yes	7.6.2.4	ABC_transporter-like_ATP-bd, AAA+_ATPase, FA_transporter
JAG2	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, VWF_dom

Expression context

Cohort genes with no expression data: 0.

5 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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
cortical plate	1
ganglionic eminence	1
ventricular zone	1
duodenum	1
jejunal mucosa	1
mucosa of transverse colon	1
quadriceps femoris	1
skeletal muscle tissue of rectus abdominis	1
vastus lateralis	1
ileal mucosa	1
left adrenal gland	1
left adrenal gland cortex	1
apex of heart	1
nipple	1
pituitary gland	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
AMN	223	broad	marker	mucosa of transverse colon, jejunal mucosa, duodenum
ADSS1	242	ubiquitous	marker	quadriceps femoris, vastus lateralis, skeletal muscle tissue of rectus abdominis
ABCD1	201	ubiquitous	marker	ileal mucosa, left adrenal gland cortex, left adrenal gland
JAG2	281	broad	marker	nipple, apex of heart, pituitary gland

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DYNC1H1	4,215
JAG2	3,546
ADSS1	2,407
ABCD1	1,181
AMN	414

Structural data

PDB: 4 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
ABCD1	P33897	14
JAG2	Q9Y219	3
AMN	Q9BXJ7	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ADSS1	Q8N142	93.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 68. Enrichment computed across 5 evidence-associated genes (5 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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective ABCD1 causes ALD	1	1142.0×	0.027	ABCD1
Defective AMN causes MGA1	1	761.3×	0.027	AMN
Defective CUBN causes MGA1	1	761.3×	0.027	AMN
Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	571.0×	0.027	JAG2
HDL clearance	1	456.8×	0.027	AMN
alpha-linolenic (omega3) and linoleic (omega6) acid metabolism	1	380.7×	0.027	ABCD1
Constitutive Signaling by NOTCH1 t(7;9)(NOTCH1:M1580_K2555) Translocation Mutant	1	326.3×	0.027	JAG2
Signaling by NOTCH1 HD Domain Mutants in Cancer	1	253.8×	0.027	JAG2
Linoleic acid (LA) metabolism	1	228.4×	0.027	ABCD1
Uptake of dietary cobalamins into enterocytes	1	228.4×	0.027	AMN
Purine ribonucleoside monophosphate biosynthesis	1	207.6×	0.027	ADSS1
Beta-oxidation of very long chain fatty acids	1	175.7×	0.027	ABCD1
Defects in cobalamin (B12) metabolism	1	163.1×	0.027	AMN
Constitutive Signaling by NOTCH1 HD Domain Mutants	1	152.3×	0.027	JAG2
Signaling by NOTCH2	1	142.8×	0.027	JAG2
alpha-linolenic acid (ALA) metabolism	1	142.8×	0.027	ABCD1
Peroxisomal lipid metabolism	1	134.3×	0.027	ABCD1
Cobalamin (Cbl, vitamin B12) transport and metabolism	1	126.9×	0.027	AMN
ABC transporters in lipid homeostasis	1	120.2×	0.027	ABCD1
Defects in vitamin and cofactor metabolism	1	120.2×	0.027	AMN
Disease	3	7.8×	0.027	AMN, ABCD1, JAG2
Signaling by NOTCH3	1	103.8×	0.028	JAG2
Class I peroxisomal membrane protein import	1	103.8×	0.028	ABCD1
Plasma lipoprotein clearance	1	95.2×	0.028	AMN
NOTCH3 Activation and Transmission of Signal to the Nucleus	1	95.2×	0.028	JAG2
NOTCH2 Activation and Transmission of Signal to the Nucleus	1	87.8×	0.028	JAG2
ABC transporter disorders	1	87.8×	0.028	ABCD1
Signaling by NOTCH1 PEST Domain Mutants in Cancer	1	81.6×	0.028	JAG2
Signaling by NOTCH1 in Cancer	1	81.6×	0.028	JAG2
Signaling by NOTCH1 HD+PEST Domain Mutants in Cancer	1	81.6×	0.028	JAG2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
epithelial cell apoptotic process involved in palatal shelf morphogenesis	1	3370.4×	0.007	JAG2
peroxisomal membrane transport	1	1685.2×	0.007	ABCD1
very long-chain fatty-acyl-CoA catabolic process	1	1685.2×	0.007	ABCD1
auditory receptor cell fate commitment	1	1123.5×	0.007	JAG2
thymic T cell selection	1	1123.5×	0.007	JAG2
renal protein absorption	1	1123.5×	0.007	AMN
positive regulation of unsaturated fatty acid biosynthetic process	1	1123.5×	0.007	ABCD1
AMP biosynthetic process	1	842.6×	0.007	ADSS1
IMP metabolic process	1	842.6×	0.007	ADSS1
sterol homeostasis	1	842.6×	0.007	ABCD1
long-chain fatty acid import into peroxisome	1	674.1×	0.007	ABCD1
regulation of metaphase plate congression	1	674.1×	0.007	DYNC1H1
regulation of fatty acid beta-oxidation	1	561.7×	0.007	ABCD1
long-chain fatty acid catabolic process	1	561.7×	0.007	ABCD1
myelin maintenance	1	561.7×	0.007	ABCD1
AMP salvage	1	561.7×	0.007	ADSS1
establishment of spindle localization	1	561.7×	0.007	DYNC1H1
regulation of mitochondrial depolarization	1	561.7×	0.007	ABCD1
fatty acid elongation	1	481.5×	0.007	ABCD1
very long-chain fatty acid catabolic process	1	481.5×	0.007	ABCD1
aspartate metabolic process	1	421.3×	0.007	ADSS1
gamma-delta T cell differentiation	1	421.3×	0.007	JAG2
‘de novo’ AMP biosynthetic process	1	421.3×	0.007	ADSS1
positive regulation of spindle assembly	1	421.3×	0.007	DYNC1H1
cobalamin transport	1	374.5×	0.008	AMN
positive regulation of intracellular transport	1	337.0×	0.008	DYNC1H1
retrograde axonal transport	1	306.4×	0.008	DYNC1H1
cobalamin metabolic process	1	306.4×	0.008	AMN
morphogenesis of embryonic epithelium	1	306.4×	0.008	JAG2
positive regulation of fatty acid beta-oxidation	1	306.4×	0.008	ABCD1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 5 evidence-associated genes (20%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
DYNC1H1	1	2
AMN	0	0
ADSS1	0	0
ABCD1	0	0
JAG2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
MOLIBRESIB	2	DYNC1H1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
DYNC1H1	7	Binding:7

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ADSS1	6.3.4.4	adenylosuccinate synthase
ABCD1	7.6.2.4	ABC-type fatty-acyl-CoA transporter

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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	DYNC1H1

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	DYNC1H1
C	Druggable family + PDB, no drug	1	ABCD1
D	Druggable family + AlphaFold only, no drug	1	ADSS1
E	Difficult family or no structure, no drug	2	AMN, JAG2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
AMN	0	—
ADSS1	0	—
ABCD1	0	—
JAG2	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