Axonal neuropathy

Summary

Axonal neuropathy (MONDO:0004183) is a disease caused by GBF1 (GenCC Strong), with 9 cohort genes and 1 clinical trial.

At a glance

• Causal gene: GBF1 (GenCC Strong)
• Cohort genes: 9
• ClinVar variants: 10
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	axonal neuropathy
Mondo ID	MONDO:0004183
DOID	DOID:7319
NCIT	C27301
SNOMED CT	60703000
UMLS	C1263857
MedGen	266071
GARD	0023865
Is cancer (heuristic)	no

Also known as: axon peripheral neuropathy · axonal neuropathy · peripheral neuropathy of axon

Data availability: 10 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 3 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › axonal neuropathy

Related subtypes (29): autoimmune neuropathy, autonomic neuropathy, mononeuropathy, ischemic neuropathy, polyneuropathy, neuritis, motor peripheral neuropathy, sensory peripheral neuropathy, uremic neuropathy, nerve compression syndrome, diabetic neuropathy, acquired peripheral neuropathy, hereditary peripheral neuropathy, neuralgia, peripheral nerve lesion, nerve plexus disorder, traumatic neuropathy, radiation-induced neuropathy, vasculitic neuropathy, chronic idiopathic neuropathy, chemotherapy-induced neuropathy, infectious neuropathy, vitamin deficiency related neuropathy, paraproteinemia-associated neuropathy, neuropathy in cryoglobulinemia, neuropathy in endocrine disorder, sarcoid neuropathy, neuropathy, small fiber, idiopathic small fibers neuropathy

Subtypes (3): giant axonal neuropathy, infantile axonal neuropathy, congenital axonal neuropathy with encephalopathy

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

10 retrieved; paginated sample, class counts are floors:

5 uncertain significance, 2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
523238	GRCh37/hg19 17p12(chr17:14215739-15422582)	CDRT4	Pathogenic	criteria provided, single submitter
4200	NM_018972.4(GDAP1):c.715C>T (p.Leu239Phe)	GDAP1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2280	NM_014874.4(MFN2):c.2119C>T (p.Arg707Trp)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
333595	NM_020919.4(ALS2):c.2479A>T (p.Thr827Ser)	ALS2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
217165	NM_014874.4(MFN2):c.707C>T (p.Thr236Met)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
374111	NM_020919.4(ALS2):c.4022G>A (p.Arg1341His)	ALS2	Uncertain significance	criteria provided, multiple submitters, no conflicts
816538	NM_006329.4(FBLN5):c.889C>G (p.His297Asp)	FBLN5	Uncertain significance	criteria provided, multiple submitters, no conflicts
374064	NM_001145809.2(MYH14):c.1945+6G>A	MYH14	Uncertain significance	criteria provided, single submitter
816539	NM_177402.5(SYT2):c.322A>G (p.Met108Val)	SYT2	Uncertain significance	criteria provided, single submitter
689544	NM_015271.5(TRIM2):c.1918G>T (p.Gly640Cys)	TRIM2	Uncertain significance	no assertion criteria provided

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 2 · Orphanet: 20 · 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
GBF1	Strong	Autosomal dominant	Charcot-Marie-Tooth Disease, axonal, type 2GG	2

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SYT2	Orphanet:98914	Presynaptic congenital myasthenic syndromes
GDAP1	Orphanet:101097	Autosomal recessive Charcot-Marie-Tooth disease with hoarseness
GDAP1	Orphanet:101102	Charcot-Marie-Tooth disease type 2H
GDAP1	Orphanet:217055	Autosomal recessive intermediate Charcot-Marie-Tooth disease type A
GDAP1	Orphanet:99944	Autosomal dominant Charcot-Marie-Tooth disease type 2K
GDAP1	Orphanet:99948	Charcot-Marie-Tooth disease type 4A
TRIM2	Orphanet:397968	Charcot-Marie-Tooth disease type 2R
MFN2	Orphanet:2398	Multiple symmetric lipomatosis
MFN2	Orphanet:64751	Hereditary motor and sensory neuropathy type 5
MFN2	Orphanet:90118	Severe early-onset axonal neuropathy due to MFN2 deficiency
MFN2	Orphanet:90120	Hereditary motor and sensory neuropathy type 6
MFN2	Orphanet:99947	Autosomal dominant Charcot-Marie-Tooth disease type 2A2
MYH14	Orphanet:397744	MYH14-related peripheral neuropathy-myopathy-hoarseness-hearing loss syndrome
MYH14	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
FBLN5	Orphanet:280598	Hereditary sensorimotor neuropathy with hyperelastic skin
FBLN5	Orphanet:90348	Autosomal dominant cutis laxa
FBLN5	Orphanet:90349	Autosomal recessive cutis laxa type 1
ALS2	Orphanet:247604	Juvenile primary lateral sclerosis
ALS2	Orphanet:293168	Infantile-onset ascending hereditary spastic paralysis
ALS2	Orphanet:300605	Juvenile amyotrophic lateral sclerosis

Cohort genes → proteins

9 cohort genes, 9 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	9

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GBF1	HGNC:4181	ENSG00000107862	Q92538	Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1	gencc
SYT2	HGNC:11510	ENSG00000143858	Q8N9I0	Synaptotagmin-2	clinvar
CDRT4	HGNC:14383	ENSG00000239704	Q8N9R6	CMT1A duplicated region transcript 4 protein	clinvar
GDAP1	HGNC:15968	ENSG00000104381	Q8TB36	Ganglioside-induced differentiation-associated protein 1	clinvar
TRIM2	HGNC:15974	ENSG00000109654	Q9C040	Tripartite motif-containing protein 2	clinvar
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	clinvar
MYH14	HGNC:23212	ENSG00000105357	Q7Z406	Myosin-14	clinvar
FBLN5	HGNC:3602	ENSG00000140092	Q9UBX5	Fibulin-5	clinvar
ALS2	HGNC:443	ENSG00000003393	Q96Q42	Alsin	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GBF1	Golgi-specific brefeldin A-resistance guanine nucleotide exchange factor 1	Guanine-nucleotide exchange factor (GEF) for members of the Arf family of small GTPases involved in trafficking in the early secretory pathway; its GEF activity initiates the coating of nascent vesicles via the localized generation of acti…
SYT2	Synaptotagmin-2	Exhibits calcium-dependent phospholipid and inositol polyphosphate binding properties.
GDAP1	Ganglioside-induced differentiation-associated protein 1	Regulates the mitochondrial network by promoting mitochondrial fission.
TRIM2	Tripartite motif-containing protein 2	UBE2D1-dependent E3 ubiquitin-protein ligase that mediates the ubiquitination of NEFL and of phosphorylated BCL2L11.
MFN2	Mitofusin-2	Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion.
MYH14	Myosin-14	Cellular myosin that appears to play a role in cytokinesis, cell shape, and specialized functions such as secretion and capping.
FBLN5	Fibulin-5	Essential for elastic fiber formation, is involved in the assembly of continuous elastin (ELN) polymer and promotes the interaction of microfibrils and ELN.
ALS2	Alsin	May act as a GTPase regulator.

Protein-family classification

Druggable: 0 · Difficult: 2 · Unknown: 7 · 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	7	1.4×	0.484
Scaffold/PPI	1	1.9×	0.623
Transcription factor	1	0.9×	0.687

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GBF1	Other/Unknown	no		Sec7_dom, ARM-type_fold, Sec7_C_sf
SYT2	Other/Unknown	no		C2_dom, Synaptotagmin, C2_domain_sf
CDRT4	Other/Unknown	no		CDRT4
GDAP1	Other/Unknown	no		Glutathione_S-Trfase_N, Glutathione-S-Trfase_C-like, GST_C_GDAP1
TRIM2	Transcription factor	no		Znf_B-box, NHL_repeat, Filamin/ABP280_rpt
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase
MYH14	Scaffold/PPI	no		IQ_motif_EF-hand-BS, Myosin_head_motor_dom-like, Myosin_tail
FBLN5	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
ALS2	Other/Unknown	no		DH_dom, Reg_chr_condens, VPS9

Expression context

Cohort genes with no expression data: 0.

6 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)	9
unknown	0

Top tissues across cohort

Tissue	Cohort genes
adenohypophysis	2
colonic epithelium	1
ventricular zone	1
olfactory bulb	1
pons	1
type B pancreatic cell	1
pituitary gland	1
right uterine tube	1
endothelial cell	1
oocyte	1
secondary oocyte	1
corpus callosum	1
dorsal motor nucleus of vagus nerve	1
inferior olivary complex	1
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
gastrocnemius	1
ileal mucosa	1
mucosa of transverse colon	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GBF1	259	ubiquitous	marker	colonic epithelium, ventricular zone, adenohypophysis
SYT2	165	tissue_specific	yes	olfactory bulb, pons, type B pancreatic cell
CDRT4	134	tissue_specific	yes	right uterine tube, pituitary gland, adenohypophysis
GDAP1	244	ubiquitous	yes	endothelial cell, secondary oocyte, oocyte
TRIM2	284	ubiquitous	marker	inferior olivary complex, dorsal motor nucleus of vagus nerve, corpus callosum
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
MYH14	227	broad	marker	mucosa of transverse colon, ileal mucosa, gastrocnemius
FBLN5	261	ubiquitous	marker	thoracic aorta, ascending aorta, descending thoracic aorta
ALS2	254	ubiquitous	marker	cerebellum, cerebellar cortex, cerebellar hemisphere

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MFN2	3,853
ALS2	2,652
GBF1	2,436
FBLN5	2,301
SYT2	1,991
MYH14	1,569
TRIM2	1,275
GDAP1	1,249
CDRT4	178

Intra-cohort edges

A	B	Sources
GDAP1	MFN2	string_interaction
GDAP1	TRIM2	string_interaction

Structural data

PDB: 5 · AlphaFold-only: 4 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GDAP1	Q8TB36	8
TRIM2	Q9C040	6
MFN2	O95140	3
MYH14	Q7Z406	2
SYT2	Q8N9I0	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FBLN5	Q9UBX5	83.69
ALS2	Q96Q42	74.69
GBF1	Q92538	71.42
CDRT4	Q8N9R6	66.42

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 52. Enrichment computed across 9 evidence-associated genes (8 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 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Toxicity of botulinum toxin type B (botB)	1	475.8×	0.048	SYT2
Miro GTPase Cycle	1	285.5×	0.048	MFN2
RHOT2 GTPase cycle	1	203.9×	0.048	MFN2
Neurotoxicity of clostridium toxins	1	178.4×	0.048	SYT2
Assembly and Release of Dengue Virus Virions	1	178.4×	0.048	GBF1
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	3	12.6×	0.048	MFN2, MYH14, ALS2
Mitophagy	1	129.8×	0.051	MFN2
Uptake and actions of bacterial toxins	1	102.0×	0.051	SYT2
Sema4D in semaphorin signaling	1	84.0×	0.051	MYH14
RHO GTPases activate CIT	1	75.1×	0.051	MYH14
RHO GTPases Activate ROCKs	1	75.1×	0.051	MYH14
Sema4D induced cell migration and growth-cone collapse	1	71.4×	0.051	MYH14
RHO GTPases activate PAKs	1	68.0×	0.051	MYH14
VxPx cargo-targeting to cilium	1	64.9×	0.051	GBF1
Class I peroxisomal membrane protein import	1	64.9×	0.051	GDAP1
Semaphorin interactions	1	49.2×	0.051	MYH14
EPHA-mediated growth cone collapse	1	47.6×	0.051	MYH14
Rab regulation of trafficking	1	46.0×	0.051	ALS2
PINK1-PRKN Mediated Mitophagy	1	44.6×	0.051	MFN2
Elastic fibre formation	1	42.0×	0.051	FBLN5
Bacterial Infection Pathways	1	42.0×	0.051	SYT2
Membrane Trafficking	2	9.3×	0.051	SYT2, ALS2
Vesicle-mediated transport	2	8.7×	0.051	SYT2, ALS2
Signaling by Rho GTPases	2	8.6×	0.051	MYH14, ALS2
RHO GTPases activate PKNs	1	39.6×	0.051	MYH14
Molecules associated with elastic fibres	1	38.6×	0.051	FBLN5
Selective autophagy	1	34.8×	0.055	MFN2
Protein-protein interactions at synapses	1	33.2×	0.055	SYT2
trans-Golgi Network Vesicle Budding	1	31.7×	0.056	GBF1
Signal Transduction	3	3.8×	0.063	MFN2, MYH14, ALS2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 8 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial fusion	2	210.7×	0.003	GDAP1, MFN2
obsolete protein targeting to mitochondrion	2	145.3×	0.004	GDAP1, MFN2
cell activation involved in immune response	1	2106.5×	0.008	GBF1
intramembranous bone growth	1	2106.5×	0.008	FBLN5
protein localization to endoplasmic reticulum tubular network	1	2106.5×	0.008	GBF1
establishment of monopolar cell polarity	1	1053.2×	0.012	GBF1
endoplasmic reticulum-Golgi intermediate compartment organization	1	1053.2×	0.012	GBF1
type 2 mitophagy	1	421.3×	0.022	MFN2
Golgi disassembly	1	351.1×	0.022	GBF1
regulation of removal of superoxide radicals	1	351.1×	0.022	FBLN5
mitochondrial membrane organization	1	300.9×	0.022	MFN2
COPI coating of Golgi vesicle	1	300.9×	0.022	GBF1
secretion	1	263.3×	0.022	FBLN5
protein localization to endoplasmic reticulum exit site	1	263.3×	0.022	GBF1
positive regulation of vascular associated smooth muscle cell apoptotic process	1	263.3×	0.022	MFN2
reactive oxygen species biosynthetic process	1	234.1×	0.022	GBF1
mitochondrion localization	1	210.7×	0.022	MFN2
regulation of protein localization to cell surface	1	210.7×	0.022	GBF1
elastic fiber assembly	1	191.5×	0.022	FBLN5
regulation of endosome size	1	191.5×	0.022	ALS2
cellular response to vitamin D	1	191.5×	0.022	GDAP1
receptor recycling	1	162.0×	0.024	ALS2
calcium-dependent activation of synaptic vesicle fusion	1	162.0×	0.024	SYT2
positive regulation of osteoblast proliferation	1	150.5×	0.024	FBLN5
mitochondrial fission	1	131.7×	0.025	GDAP1
post-Golgi vesicle-mediated transport	1	131.7×	0.025	GBF1
Golgi to endosome transport	1	131.7×	0.025	GBF1
protein localization to phagophore assembly site	1	123.9×	0.025	MFN2
regulation of calcium ion-dependent exocytosis	1	117.0×	0.026	SYT2
regulation of ARF protein signal transduction	1	110.9×	0.026	GBF1

Therapeutics

Drug target analysis

Approved (phase 4): 1 · Phase ≥3: 1 · Phased (≥1): 1 · Undrugged: 8

Druggability breadth: 2 of 9 evidence-associated genes (22%) 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
MYH14	TUCATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MYH14	1	4
GBF1	0	0
SYT2	0	0
CDRT4	0	0
GDAP1	0	0
TRIM2	0	0
MFN2	0	0
FBLN5	0	0
ALS2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
TUCATINIB	4	MYH14

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
MFN2	3	Binding:3
MYH14	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 9; 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)
TUCATINIB	4	MYH14

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	MYH14
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	8	GBF1, SYT2, CDRT4, GDAP1, TRIM2, MFN2, FBLN5, ALS2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GBF1	0	—
SYT2	0	—
CDRT4	0	—
GDAP1	0	—
TRIM2	0	—
MFN2	3	—
FBLN5	0	—
ALS2	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
NCT01847937	Not specified	COMPLETED	Magnetic Resonance Diagnostics of Diabetic Peripheral Neuropathy