Hereditary motor and sensory neuropathy

Summary

Hereditary motor and sensory neuropathy (MONDO:0015358) is a disease (an umbrella term covering 8 Mondo subtypes) caused by MFN2 (GenCC Strong), with 6 cohort genes and 4 clinical trials. Top therapeutic interventions include ascorbic acid.

At a glance

• Causal gene: MFN2 (GenCC Strong)
• Umbrella term: 8 Mondo subtypes
• Cohort genes: 6
• ClinVar variants: 5
• Clinical trials: 4

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary motor and sensory neuropathy
Mondo ID	MONDO:0015358
MeSH	D015417
Orphanet	140450
ICD-10-CM	G60.0
ICD-11	1538134578
SNOMED CT	398100001
UMLS	C0027888
MedGen	45066
GARD	0012685
Is cancer (heuristic)	no

Also known as: HMSN

Data availability: 5 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 8 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › peripheral nervous system disorder › peripheral neuropathy › hereditary peripheral neuropathy › hereditary motor and sensory neuropathy

Related subtypes (64): giant axonal neuropathy, Finnish type amyloidosis, familial amyloid neuropathy, carpal tunnel syndrome, congenital trigeminal anesthesia, familial recurrent peripheral facial palsy, meralgia paraesthetica, familial, amyotrophic neuralgia, hereditary neuropathy with liability to pressure palsies, abetalipoproteinemia, VPS13A-related neurodegenerative disease, mitochondrial DNA depletion syndrome 4a, oxoglutaricaciduria, cerebrotendinous xanthomatosis, Chediak-Higashi syndrome, homocystinuria due to methylene tetrahydrofolate reductase deficiency, Krabbe disease, beta-mannosidosis, biotinidase deficiency, Leigh syndrome, hereditary sensory and autonomic neuropathy with spastic paraplegia, ornithine aminotransferase deficiency, adult polyglucosan body disease, Sandhoff disease, Tay-Sachs disease, methylmalonic aciduria and homocystinuria type cblC, familial isolated deficiency of vitamin E, Kearns-Sayre syndrome, NARP syndrome, Charcot-Marie-Tooth disease type 5, hereditary motor and sensory neuropathy, Okinawa type, fumaric aciduria, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 1, sensory ataxic neuropathy, dysarthria, and ophthalmoparesis, Niemann-Pick disease type B, long chain 3-hydroxyacyl-CoA dehydrogenase deficiency, primary CD59 deficiency, PHARC syndrome, progressive demyelinating neuropathy with bilateral striatal necrosis, cataract-growth hormone deficiency-sensory neuropathy-sensorineural hearing loss-skeletal dysplasia syndrome, ataxia - oculomotor apraxia type 4, adrenomyeloneuropathy, neuropathy with hearing impairment, hereditary sensory and autonomic neuropathy, Charcot-Marie-Tooth disease, infantile axonal neuropathy, mitochondrial neurogastrointestinal encephalomyopathy, attenuated Chédiak-Higashi syndrome, coenzyme Q10 deficiency, familial episodic pain syndrome, non-progressive predominantly posterior cavitating leukoencephalopathy with peripheral neuropathy, metachromatic leukodystrophy, distal hereditary motor neuropathy, spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2, proximal spinal muscular atrophy, pyruvate dehydrogenase deficiency, peroxisome biogenesis disorder, neurodegeneration with brain iron accumulation 2A, neuropathy, congenital hypomelinating, optic atrophy-ataxia-peripheral neuropathy-global developmental delay syndrome, EMILIN-1-related connective tissue disease, PRPS1 deficiency disorder, neuropathy, hereditary sensory and autonomic, type IId, peripheral motor neuropathy, childhood-onset, biotin-responsive

Subtypes (8): polyneuropathy-hand defect syndrome, hereditary thermosensitive neuropathy, autosomal dominant slowed nerve conduction velocity, hereditary sensorimotor neuropathy with hyperelastic skin, demyelinating hereditary motor and sensory neuropathy, severe early-onset axonal neuropathy due to MFN2 deficiency, hereditary motor and sensory neuropathy with acrodystrophy, hereditary motor and sensory neuropathy type 6

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

5 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
139652	NM_001376.5(DYNC1H1):c.1792C>T (p.Arg598Cys)	DYNC1H1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
351908	NM_024577.4(SH3TC2):c.1942C>T (p.Arg648Trp)	SH3TC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
653815	NM_024577.4(SH3TC2):c.289G>A (p.Ala97Thr)	SH3TC2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2775411	NM_001939.3(DRP2):c.1698+5G>C	DRP2	Uncertain significance	criteria provided, single submitter
2775410	NM_018979.4(WNK1):c.7124del (p.Pro2375fs)	WNK1	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · 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
MFN2	Definitive	Semidominant	axonal hereditary motor and sensory neuropathy	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
WNK1	Orphanet:88940	Pseudohypoaldosteronism type 2C
WNK1	Orphanet:970	Hereditary sensory and autonomic neuropathy type 2
SH3TC2	Orphanet:99949	Charcot-Marie-Tooth disease type 4C
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
DPYSL2	Orphanet:178469	Autosomal dominant non-syndromic intellectual disability

Cohort genes → proteins

6 cohort genes, 6 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	6

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	gencc
WNK1	HGNC:14540	ENSG00000060237	Q9H4A3	Serine/threonine-protein kinase WNK1	clinvar
SH3TC2	HGNC:29427	ENSG00000169247	Q8TF17	SH3 domain and tetratricopeptide repeat-containing protein 2	clinvar
DYNC1H1	HGNC:2961	ENSG00000197102	Q14204	Cytoplasmic dynein 1 heavy chain 1	clinvar
DPYSL2	HGNC:3014	ENSG00000092964	Q16555	Dihydropyrimidinase-related protein 2	clinvar
DRP2	HGNC:3032	ENSG00000102385	Q13474	Dystrophin-related protein 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
MFN2	Mitofusin-2	Mitochondrial outer membrane GTPase that mediates mitochondrial clustering and fusion.
WNK1	Serine/threonine-protein kinase WNK1	Serine/threonine-protein kinase component of the WNK1-SPAK/OSR1 kinase cascade, which acts as a key regulator of blood pressure and regulatory volume increase by promoting ion influx.
SH3TC2	SH3 domain and tetratricopeptide repeat-containing protein 2	Is involved in nerve myelination and is required for the integrity of nodes of Ranvier.
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.
DPYSL2	Dihydropyrimidinase-related protein 2	Plays a role in neuronal development and polarity, as well as in axon growth and guidance, neuronal growth cone collapse and cell migration.
DRP2	Dystrophin-related protein 2	Required for normal myelination and for normal organization of the cytoplasm and the formation of Cajal bands in myelinating Schwann cells.

Protein-family classification

Druggable: 1 · Difficult: 2 · Unknown: 3 · Druggable fraction: 0.17

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	4.6×	0.601
Scaffold/PPI	1	2.9×	0.601
Transcription factor	1	1.4×	0.719
Other/Unknown	3	0.9×	0.758

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase
WNK1	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_sf
SH3TC2	Scaffold/PPI	no		SH3_domain, TPR-like_helical_dom_sf, TPR_rpt
DYNC1H1	Other/Unknown	no		AAA+_ATPase, Dhc_D6_P-loop, Dynein_heavy_tail
DPYSL2	Other/Unknown	no		Amidohydro-rel, Metal-dep_hydrolase_composite, Hydantoinase/dihydroPyrase
DRP2	Transcription factor	no		Znf_ZZ, WW_dom, Spectrin_repeat

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)	6
unknown	0

Top tissues across cohort

Tissue	Cohort genes
inferior vagus X ganglion	2
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
globus pallidus	1
medial globus pallidus	1
C1 segment of cervical spinal cord	1
corpus callosum	1
sural nerve	1
cortical plate	1
ganglionic eminence	1
ventricular zone	1
substantia nigra pars compacta	1
subthalamic nucleus	1
dorsal root ganglion	1
tibial nerve	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
MFN2	297	ubiquitous	marker	apex of heart, heart left ventricle, cardiac ventricle
WNK1	297	ubiquitous	marker	medial globus pallidus, globus pallidus, inferior vagus X ganglion
SH3TC2	168	broad	marker	corpus callosum, sural nerve, C1 segment of cervical spinal cord
DYNC1H1	290	ubiquitous	marker	cortical plate, ganglionic eminence, ventricular zone
DPYSL2	301	ubiquitous	marker	inferior vagus X ganglion, subthalamic nucleus, substantia nigra pars compacta
DRP2	151	broad	marker	trigeminal ganglion, tibial nerve, dorsal root ganglion

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
DYNC1H1	4,215
MFN2	3,853
DPYSL2	2,980
DRP2	637
SH3TC2	569
WNK1	371

Structural data

PDB: 4 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
DYNC1H1	Q14204	97
DPYSL2	Q16555	15
WNK1	Q9H4A3	5
MFN2	O95140	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
SH3TC2	Q8TF17	78.63
DRP2	Q13474	74.10

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 36. Enrichment computed across 6 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
Miro GTPase Cycle	1	456.8×	0.055	MFN2
RHOT2 GTPase cycle	1	326.3×	0.055	MFN2
Mitophagy	1	207.6×	0.058	MFN2
CRMPs in Sema3A signaling	1	126.9×	0.067	DPYSL2
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	73.7×	0.067	DRP2
PINK1-PRKN Mediated Mitophagy	1	71.4×	0.067	MFN2
Formation of the dystrophin-glycoprotein complex (DGC)	1	61.7×	0.067	DRP2
Selective autophagy	1	55.7×	0.067	MFN2
Aggrephagy	1	49.6×	0.067	DYNC1H1
Recycling pathway of L1	1	44.8×	0.067	DPYSL2
COPI-independent Golgi-to-ER retrograde traffic	1	41.5×	0.067	DYNC1H1
HSP90 chaperone cycle for steroid hormone receptors (SHR) in the presence of ligand	1	38.7×	0.067	DYNC1H1
Loss of Nlp from mitotic centrosomes	1	31.7×	0.067	DYNC1H1
Loss of proteins required for interphase microtubule organization from the centrosome	1	31.7×	0.067	DYNC1H1
AURKA Activation by TPX2	1	30.4×	0.067	DYNC1H1
Autophagy	1	29.7×	0.067	MFN2
Stimuli-sensing channels	1	27.2×	0.067	WNK1
Recruitment of mitotic centrosome proteins and complexes	1	27.2×	0.067	DYNC1H1
Regulation of PLK1 Activity at G2/M Transition	1	25.4×	0.067	DYNC1H1
Amplification of signal from unattached kinetochores via a MAD2 inhibitory signal	1	23.3×	0.067	DYNC1H1
Recruitment of NuMA to mitotic centrosomes	1	23.3×	0.067	DYNC1H1
Macroautophagy	1	23.1×	0.067	MFN2
Anchoring of the basal body to the plasma membrane	1	22.6×	0.067	DYNC1H1
COPI-mediated anterograde transport	1	22.0×	0.067	DYNC1H1
EML4 and NUDC in mitotic spindle formation	1	18.6×	0.075	DYNC1H1
MHC class II antigen presentation	1	17.8×	0.075	DYNC1H1
Resolution of Sister Chromatid Cohesion	1	17.3×	0.075	DYNC1H1
HCMV Early Events	1	16.2×	0.077	DYNC1H1
RHO GTPases Activate Formins	1	15.5×	0.078	DYNC1H1
Mitotic Prometaphase	1	13.8×	0.084	DYNC1H1

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 6 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of ERBB signaling pathway	1	2808.7×	0.011	SH3TC2
positive regulation of termination of RNA polymerase II transcription	1	2808.7×	0.011	WNK1
negative regulation of cell-cell adhesion mediated by integrin	1	1404.3×	0.011	WNK1
monoatomic cation homeostasis	1	1404.3×	0.011	WNK1
chemokine (C-C motif) ligand 21 signaling pathway	1	702.2×	0.011	WNK1
lymphocyte migration into lymph node	1	702.2×	0.011	WNK1
type 2 mitophagy	1	561.7×	0.011	MFN2
negative regulation of pancreatic juice secretion	1	561.7×	0.011	WNK1
regulation of metaphase plate congression	1	561.7×	0.011	DYNC1H1
negative regulation of sodium ion transport	1	468.1×	0.011	WNK1
regulation of intracellular protein transport	1	468.1×	0.011	SH3TC2
establishment of spindle localization	1	468.1×	0.011	DYNC1H1
negative regulation of leukocyte cell-cell adhesion	1	468.1×	0.011	WNK1
positive regulation of mitotic cytokinesis	1	468.1×	0.011	WNK1
mitochondrial membrane organization	1	401.2×	0.011	MFN2
regulation of mRNA export from nucleus	1	351.1×	0.011	WNK1
regulation of monoatomic cation transmembrane transport	1	351.1×	0.011	WNK1
positive regulation of vascular associated smooth muscle cell apoptotic process	1	351.1×	0.011	MFN2
positive regulation of spindle assembly	1	351.1×	0.011	DYNC1H1
negative regulation of heterotypic cell-cell adhesion	1	312.1×	0.011	WNK1
intracellular chloride ion homeostasis	1	280.9×	0.011	WNK1
positive regulation of intracellular transport	1	280.9×	0.011	DYNC1H1
mitochondrion localization	1	280.9×	0.011	MFN2
regulation of endocytic recycling	1	280.9×	0.011	SH3TC2
retrograde axonal transport	1	255.3×	0.011	DYNC1H1
peripheral nervous system myelin maintenance	1	255.3×	0.011	SH3TC2
protein insertion into ER membrane by stop-transfer membrane-anchor sequence	1	255.3×	0.011	WNK1
synaptic signaling	1	255.3×	0.011	DRP2
positive regulation of cold-induced thermogenesis	2	54.5×	0.011	MFN2, DYNC1H1
positive regulation of systemic arterial blood pressure	1	234.1×	0.011	WNK1

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 1 · Undrugged: 5

Druggability breadth: 4 of 6 evidence-associated genes (67%) 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
MFN2	0	0
WNK1	0	0
SH3TC2	0	0
DPYSL2	0	0
DRP2	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): 0.

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

Symbol	Assays	Type breakdown
WNK1	165	Binding:165
DYNC1H1	7	Binding:7
MFN2	3	Binding:3
DPYSL2	3	Binding:3

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
WNK1	165

Pharmacogenomics

Cohort genes with a PharmGKB record: 6; 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	WNK1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	4	MFN2, SH3TC2, DPYSL2, DRP2

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
WNK1	165	—
MFN2	3	—
SH3TC2	0	—
DPYSL2	3	—
DRP2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01193088	Not specified	RECRUITING	Genetics of Charcot Marie Tooth (CMT) - Modifiers of CMT1A, New Causes of CMT2
NCT07072676	Not specified	ENROLLING_BY_INVITATION	The Use of Assistive Gait Devices Can Reduce the Risk of Falls in Patients With Neuromuscular Diseases Following a Training Period.
NCT04461613	Not specified	UNKNOWN	Physical Activity in Persons With Charcot-Marie-Tooth: Developing a Measurement Instrument

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ASCORBIC ACID	4	1