Hereditary motor and sensory neuropathy type 6

Summary

Hereditary motor and sensory neuropathy type 6 (MONDO:0019551) is a disease with 3 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 3
• ClinVar variants: 116

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		73	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary motor and sensory neuropathy type 6
Mondo ID	MONDO:0019551
Orphanet	90120
DOID	DOID:0080068
ICD-11	467894833
UMLS	C0393807
MedGen	140747
GARD	0016787
Is cancer (heuristic)	no

Also known as: Charcot-Marie-Tooth disease type 6 · CMT6 · hereditary motor and sensory neuropathy type 6 · peripheral neuropathy and optic atrophy

Data availability: 116 ClinVar variants · 2 GenCC gene-disease records.

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 › hereditary peripheral neuropathy › hereditary motor and sensory neuropathy › hereditary motor and sensory neuropathy type 6

Related subtypes (7): 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

Subtypes (3): neuropathy, hereditary motor and sensory, type 6A, neuropathy, hereditary motor and sensory, type 6B, neuropathy, hereditary motor and sensory, type VIc, with optic atrophy

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

116 retrieved; paginated sample, class counts are floors:

38 uncertain significance, 25 benign, 21 benign/likely benign, 18 conflicting classifications of pathogenicity, 5 pathogenic/likely pathogenic, 4 pathogenic, 3 likely pathogenic, 1 not provided, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
217161	NM_014874.4(MFN2):c.1126A>G (p.Met376Val)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2269	NM_014874.4(MFN2):c.2219G>C (p.Trp740Ser)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2276	NM_014874.4(MFN2):c.280C>T (p.Arg94Trp)	MFN2	Pathogenic	criteria provided, multiple submitters, no conflicts
2278	NM_014874.4(MFN2):c.1090C>T (p.Arg364Trp)	MFN2	Pathogenic	criteria provided, multiple submitters, no conflicts
2279	NM_014874.4(MFN2):c.617C>T (p.Thr206Ile)	MFN2	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
2281	NM_014874.4(MFN2):c.310C>T (p.Arg104Trp)	MFN2	Pathogenic	criteria provided, multiple submitters, no conflicts
30738	NM_014874.4(MFN2):c.1085C>T (p.Thr362Met)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
372790	NM_014874.4(MFN2):c.1252C>T (p.Arg418Ter)	MFN2	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
437424	NM_014874.4(MFN2):c.720C>G (p.Phe240Leu)	MFN2	Likely pathogenic	criteria provided, single submitter
488546	NM_014874.4(MFN2):c.1839dup (p.Thr614fs)	MFN2	Likely pathogenic	criteria provided, single submitter
1048600	NM_152269.5(MTRFR):c.18_21del (p.Leu6fs)	MTRFR	Likely pathogenic	criteria provided, single submitter
198868	NM_014874.4(MFN2):c.756C>T (p.Asn252=)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214642	NM_014874.4(MFN2):c.842G>C (p.Cys281Ser)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214643	NM_014874.4(MFN2):c.898C>T (p.Arg300Cys)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214648	NM_014874.4(MFN2):c.1987C>T (p.Arg663Cys)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214649	NM_014874.4(MFN2):c.2146G>A (p.Ala716Thr)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
214656	NM_014874.4(MFN2):c.58C>T (p.His20Tyr)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
219952	NM_014874.4(MFN2):c.1920C>G (p.Leu640=)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2277	NM_014874.4(MFN2):c.827A>G (p.Gln276Arg)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
2282	NM_014874.4(MFN2):c.1403G>A (p.Arg468His)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
246508	NM_014874.4(MFN2):c.179C>T (p.Thr60Met)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292372	NM_014874.4(MFN2):c.474+4A>G	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292374	NM_014874.4(MFN2):c.1269G>A (p.Thr423=)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
292378	NM_014874.4(MFN2):c.2145C>T (p.Ala715=)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
378135	NM_014874.4(MFN2):c.2157G>A (p.Lys719=)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
873747	NM_014874.4(MFN2):c.205G>A (p.Val69Ile)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
873853	NM_014874.4(MFN2):c.2204+13C>T	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
874760	NM_014874.4(MFN2):c.1716+8A>G	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
875697	NM_014874.4(MFN2):c.1938C>A (p.Val646=)	MFN2	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · 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
MFN2	Definitive	Semidominant	axonal hereditary motor and sensory neuropathy	11
SLC25A46	Definitive	Autosomal recessive	neuropathy, hereditary motor and sensory, type 6B	8

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
SLC25A46	Orphanet:2254	Pontocerebellar hypoplasia type 1
SLC25A46	Orphanet:90120	Hereditary motor and sensory neuropathy type 6
MTRFR	Orphanet:254930	Combined oxidative phosphorylation defect type 7
MTRFR	Orphanet:320375	Autosomal recessive spastic paraplegia type 55

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
MFN2	HGNC:16877	ENSG00000116688	O95140	Mitofusin-2	gencc,clinvar
SLC25A46	HGNC:25198	ENSG00000164209	Q96AG3	Mitochondrial outer membrane protein SLC25A46	gencc
MTRFR	HGNC:26784	ENSG00000130921	Q9H3J6	Mitochondrial translation release factor in rescue	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.
SLC25A46	Mitochondrial outer membrane protein SLC25A46	Transmembrane protein of the mitochondrial outer membrane that controls mitochondrial organization.
MTRFR	Mitochondrial translation release factor in rescue	Part of a mitoribosome-associated quality control pathway that prevents aberrant translation by responding to interruptions during elongation.

Protein-family classification

Druggable: 0 · Difficult: 0 · Unknown: 3 · 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	3	1.8×	0.174

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
MFN2	Other/Unknown	no		Fzo/mitofusin_HR2, Mitofusin_fam, P-loop_NTPase
SLC25A46	Other/Unknown	no		MCP_transmembrane, MCP_dom_sf, SLC25A46
MTRFR	Other/Unknown	no		Pep_chain_release_fac_I, Pep_chain_release_fac_I_sf, Mito_Transl_Release_Factor

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
oocyte	2
apex of heart	1
cardiac ventricle	1
heart left ventricle	1
secondary oocyte	1
sperm	1
pancreatic ductal cell	1
thymus	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
SLC25A46	290	ubiquitous	marker	sperm, secondary oocyte, oocyte
MTRFR	250	ubiquitous	marker	thymus, oocyte, pancreatic ductal cell

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
MFN2	3,853
MTRFR	2,061
SLC25A46	1,557

Intra-cohort edges

A	B	Sources
MFN2	SLC25A46	biogrid_interaction, string_interaction

Structural data

PDB: 3 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MFN2	O95140	3
SLC25A46	Q96AG3	1
MTRFR	Q9H3J6	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 12. Enrichment computed across 3 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
Miro GTPase Cycle	1	1142.0×	0.007	MFN2
RHOT2 GTPase cycle	1	815.7×	0.007	MFN2
Mitophagy	1	519.1×	0.008	MFN2
PINK1-PRKN Mediated Mitophagy	1	178.4×	0.017	MFN2
Selective autophagy	1	139.3×	0.017	MFN2
Autophagy	1	74.2×	0.026	MFN2
Mitochondrial ribosome-associated quality control	1	61.4×	0.026	MTRFR
Macroautophagy	1	57.7×	0.026	MFN2
Factors involved in megakaryocyte development and platelet production	1	33.2×	0.040	MFN2
Hemostasis	1	18.0×	0.064	MFN2
Signaling by Rho GTPases, Miro GTPases and RHOBTB3	1	16.7×	0.064	MFN2
Signal Transduction	1	5.1×	0.187	MFN2

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
mitochondrial membrane fission	1	2808.7×	0.006	SLC25A46
peripheral nervous system neuron axonogenesis	1	1404.3×	0.006	SLC25A46
type 2 mitophagy	1	1123.5×	0.006	MFN2
mitochondrial translational termination	1	1123.5×	0.006	MTRFR
mitochondrial membrane organization	1	802.5×	0.006	MFN2
respiratory chain complex IV assembly	1	802.5×	0.006	SLC25A46
locomotion involved in locomotory behavior	1	802.5×	0.006	SLC25A46
positive regulation of vascular associated smooth muscle cell apoptotic process	1	702.2×	0.006	MFN2
mitochondrion localization	1	561.7×	0.006	MFN2
mitochondrial transport	1	401.2×	0.006	SLC25A46
optic nerve development	1	401.2×	0.006	SLC25A46
mitochondrial fission	1	351.1×	0.006	SLC25A46
cerebellar Purkinje cell differentiation	1	351.1×	0.006	SLC25A46
cristae formation	1	351.1×	0.006	SLC25A46
protein localization to phagophore assembly site	1	330.4×	0.006	MFN2
phospholipid homeostasis	1	330.4×	0.006	SLC25A46
myelination in peripheral nervous system	1	295.6×	0.007	SLC25A46
mitochondrial fusion	1	280.9×	0.007	MFN2
blastocyst formation	1	255.3×	0.007	MFN2
camera-type eye morphogenesis	1	255.3×	0.007	MFN2
autophagy of mitochondrion	1	244.2×	0.007	SLC25A46
negative regulation of Ras protein signal transduction	1	224.7×	0.007	MFN2
negative regulation of smooth muscle cell proliferation	1	208.1×	0.007	MFN2
obsolete protein targeting to mitochondrion	1	193.7×	0.007	MFN2
rescue of stalled cytosolic ribosome	1	160.5×	0.008	MTRFR
axon development	1	151.8×	0.009	SLC25A46
positive regulation of vascular associated smooth muscle cell proliferation	1	144.0×	0.009	MFN2
dendrite development	1	130.6×	0.009	SLC25A46
response to unfolded protein	1	100.3×	0.012	MFN2
aerobic respiration	1	82.6×	0.014	MFN2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
MFN2	0	0
SLC25A46	0	0
MTRFR	0	0

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

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; with CPIC/DPWG dosing guidelines: 0.

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

Chemical tractability of cohort targets

0 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.

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	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	MFN2, SLC25A46, MTRFR

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
MFN2	3	—
SLC25A46	0	—
MTRFR	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.