Distal hereditary motor neuropathy type 2

Summary

Distal hereditary motor neuropathy type 2 (MONDO:0015352) is a disease with 5 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 5
• ClinVar variants: 712

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		4	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Identifiers

Disease identifiers

Field	Value
Canonical name	distal hereditary motor neuropathy type 2
Mondo ID	MONDO:0015352
MeSH	C580044
Orphanet	139525
DOID	DOID:0111206
ICD-11	152961055
UMLS	C3711384
MedGen	777992
GARD	0016954
Is cancer (heuristic)	no

Also known as: dHMN2 · distal spinal muscular atrophy type 2 · dSMA2

Data availability: 712 ClinVar variants · 4 GenCC gene-disease records.

Disease family

An umbrella term covering 4 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › autosomal genetic disease › autosomal dominant disease › neuronopathy, distal hereditary motor, autosomal dominant › distal hereditary motor neuropathy type 2

Related subtypes (10): neuronopathy, distal hereditary motor, autosomal dominant 1, hereditary spastic paraplegia 17, neuronopathy, distal hereditary motor, autosomal dominant 8, distal hereditary motor neuropathy type 7, neuronopathy, distal hereditary motor, type 9, neuronopathy, distal hereditary motor, type 5, neuronopathy, distal hereditary motor, autosomal dominant 10, neuronopathy, distal hereditary motor, autosomal dominant 11, myopathy, myofibrillar, 13, with rimmed vacuoles, neuronopathy, distal hereditary motor, autosomal dominant 15

Subtypes (4): neuronopathy, distal hereditary motor, type 2A, neuronopathy, distal hereditary motor, type 2B, neuronopathy, distal hereditary motor, type 2C, neuronopathy, distal hereditary motor, type 2D

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:

311 uncertain significance, 250 likely benign, 21 benign, 11 conflicting classifications of pathogenicity, 5 benign/likely benign, 1 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
220419	NM_001540.5(HSPB1):c.250G>C (p.Gly84Arg)	HSPB1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
14181	NM_000530.8(MPZ):c.371C>T (p.Thr124Met)	MPZ	Pathogenic	criteria provided, multiple submitters, no conflicts
1045555	NM_205836.3(FBXO38):c.91A>C (p.Asn31His)	FBXO38	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1788669	NM_205836.3(FBXO38):c.2263G>A (p.Gly755Ser)	FBXO38	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
4684865	NM_205836.3(FBXO38):c.1715T>C (p.Val572Ala)	FBXO38	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
473948	NM_205836.3(FBXO38):c.1394G>A (p.Arg465His)	FBXO38	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
473949	NM_205836.3(FBXO38):c.1834G>A (p.Val612Ile)	FBXO38	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
473950	NM_205836.3(FBXO38):c.1862G>A (p.Arg621His)	FBXO38	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
473952	NM_205836.3(FBXO38):c.2146A>G (p.Ser716Gly)	FBXO38	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
473960	NM_205836.3(FBXO38):c.561A>G (p.Ile187Met)	FBXO38	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
511006	NM_205836.3(FBXO38):c.3024+6G>A	FBXO38	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
541015	NM_205836.3(FBXO38):c.11G>A (p.Arg4Gln)	FBXO38	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
574698	NM_205836.3(FBXO38):c.2675G>A (p.Arg892His)	FBXO38	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1001185	NM_205836.3(FBXO38):c.2182G>A (p.Val728Ile)	FBXO38	Uncertain significance	criteria provided, single submitter
1001987	NM_205836.3(FBXO38):c.812G>A (p.Arg271Gln)	FBXO38	Uncertain significance	criteria provided, multiple submitters, no conflicts
1002325	NM_205836.3(FBXO38):c.2433G>A (p.Thr811=)	FBXO38	Uncertain significance	criteria provided, single submitter
1007794	NM_205836.3(FBXO38):c.3024+5C>T	FBXO38	Uncertain significance	criteria provided, multiple submitters, no conflicts
1008505	NM_205836.3(FBXO38):c.2072T>C (p.Ile691Thr)	FBXO38	Uncertain significance	criteria provided, multiple submitters, no conflicts
1008680	NM_205836.3(FBXO38):c.529A>G (p.Ile177Val)	FBXO38	Uncertain significance	criteria provided, single submitter
1014068	NM_205836.3(FBXO38):c.1774T>G (p.Ser592Ala)	FBXO38	Uncertain significance	criteria provided, single submitter
1015340	NM_205836.3(FBXO38):c.199T>A (p.Tyr67Asn)	FBXO38	Uncertain significance	criteria provided, single submitter
1016157	NM_205836.3(FBXO38):c.1537C>G (p.His513Asp)	FBXO38	Uncertain significance	criteria provided, single submitter
1019196	NM_205836.3(FBXO38):c.871G>A (p.Gly291Ser)	FBXO38	Uncertain significance	criteria provided, single submitter
1023704	NM_205836.3(FBXO38):c.218_247del (p.Val73_Trp82del)	FBXO38	Uncertain significance	criteria provided, single submitter
1023991	NM_205836.3(FBXO38):c.3482A>C (p.Lys1161Thr)	FBXO38	Uncertain significance	criteria provided, multiple submitters, no conflicts
1024081	NM_205836.3(FBXO38):c.625A>G (p.Met209Val)	FBXO38	Uncertain significance	criteria provided, multiple submitters, no conflicts
1024303	NM_205836.3(FBXO38):c.1A>G (p.Met1Val)	FBXO38	Uncertain significance	criteria provided, single submitter
1024503	NM_205836.3(FBXO38):c.1729G>C (p.Glu577Gln)	FBXO38	Uncertain significance	criteria provided, single submitter
1034852	NM_205836.3(FBXO38):c.3130C>T (p.Arg1044Cys)	FBXO38	Uncertain significance	criteria provided, single submitter
1046325	NM_205836.3(FBXO38):c.1861C>T (p.Arg621Cys)	FBXO38	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 15 · 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
FBXO38	Strong	Autosomal dominant	neuronopathy, distal hereditary motor, type 2D	5
HSPB8	Strong	Autosomal dominant	neuronopathy, distal hereditary motor, type 2A	8
HSPB1	Moderate	Autosomal dominant	neuronopathy, distal hereditary motor, type 2B	7
HSPB3	Supportive	Autosomal dominant	distal hereditary motor neuropathy type 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
FBXO38	Orphanet:139525	Distal hereditary motor neuropathy type 2
HSPB1	Orphanet:139525	Distal hereditary motor neuropathy type 2
HSPB1	Orphanet:99940	Autosomal dominant Charcot-Marie-Tooth disease type 2F
HSPB8	Orphanet:139525	Distal hereditary motor neuropathy type 2
HSPB8	Orphanet:476093	HSPB8-related autosomal dominant distal axonal motor neuropathy-myofibrillar myopathy syndrome
HSPB8	Orphanet:99945	Autosomal dominant Charcot-Marie-Tooth disease type 2L
HSPB3	Orphanet:139525	Distal hereditary motor neuropathy type 2
MPZ	Orphanet:100046	Autosomal dominant intermediate Charcot-Marie-Tooth disease type D
MPZ	Orphanet:101082	Charcot-Marie-Tooth disease type 1B
MPZ	Orphanet:3115	Roussy-Lévy syndrome
MPZ	Orphanet:324585	Autosomal dominant intermediate Charcot-Marie-Tooth disease with neuropathic pain
MPZ	Orphanet:538574	Palmoplantar keratoderma-hereditary motor and sensory neuropathy syndrome
MPZ	Orphanet:64748	Dejerine-Sottas syndrome
MPZ	Orphanet:99942	Autosomal dominant Charcot-Marie-Tooth disease type 2I
MPZ	Orphanet:99943	Autosomal dominant Charcot-Marie-Tooth disease type 2J

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
FBXO38	HGNC:28844	ENSG00000145868	Q6PIJ6	F-box only protein 38	gencc,clinvar
HSPB1	HGNC:5246	ENSG00000106211	P04792	Heat shock protein beta-1	gencc,clinvar
HSPB8	HGNC:30171	ENSG00000152137	Q9UJY1	Heat shock protein beta-8	gencc
HSPB3	HGNC:5248	ENSG00000169271	Q12988	Heat shock protein beta-3	gencc
MPZ	HGNC:7225	ENSG00000158887	P25189	Myelin protein P0	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
FBXO38	F-box only protein 38	Substrate recognition component of a SCF (SKP1-CUL1-F-box protein) E3 ubiquitin-protein ligase complex which mediates the ubiquitination and subsequent proteasomal degradation of PDCD1/PD-1, thereby regulating T-cells-mediated immunity.
HSPB1	Heat shock protein beta-1	Small heat shock protein which functions as a molecular chaperone probably maintaining denatured proteins in a folding-competent state.
HSPB8	Heat shock protein beta-8	Involved in the chaperone-assisted selective autophagy (CASA), a crucial process for protein quality control, particularly in mechanical strained cells and tissues such as muscle.
HSPB3	Heat shock protein beta-3	Inhibitor of actin polymerization.
MPZ	Myelin protein P0	Is an adhesion molecule necessary for normal myelination in the peripheral nervous system.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 4 · Druggable fraction: 0.2

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
Antibody/Immunoglobulin	1	5.8×	0.269
Other/Unknown	4	1.4×	0.269

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FBXO38	Other/Unknown	no		F-box_dom, LRR_dom_sf, F-box-like_dom_sf
HSPB1	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone
HSPB8	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone
HSPB3	Other/Unknown	no		Alpha-crystallin/sHSP_animal, A-crystallin/Hsp20_dom, HSP20-like_chaperone
MPZ	Antibody/Immunoglobulin	yes		Myelin_P0-rel, Ig_sub, Ig-like_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
adrenal tissue	1
calcaneal tendon	1
endothelial cell	1
ascending aorta	1
lower esophagus mucosa	1
thoracic aorta	1
gastrocnemius	1
mucosa of stomach	1
skeletal muscle tissue of rectus abdominis	1
heart right ventricle	1
left ventricle myocardium	1
myocardium	1
olfactory bulb	1
sural nerve	1
tibial nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBXO38	287	ubiquitous	marker	calcaneal tendon, adrenal tissue, endothelial cell
HSPB1	299	ubiquitous	marker	lower esophagus mucosa, ascending aorta, thoracic aorta
HSPB8	284	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, mucosa of stomach, gastrocnemius
HSPB3	189	broad	marker	heart right ventricle, left ventricle myocardium, myocardium
MPZ	178	ubiquitous	marker	tibial nerve, sural nerve, olfactory bulb

Protein interactions among cohort

Intra-cohort edges: 2.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
HSPB1	5,491
HSPB3	2,711
HSPB8	1,916
FBXO38	1,732
MPZ	25

Intra-cohort edges

A	B	Sources
HSPB1	HSPB8	string_interaction
HSPB3	HSPB8	intact, string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
HSPB1	P04792	6
MPZ	P25189	2
HSPB8	Q9UJY1	1
HSPB3	Q12988	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FBXO38	Q6PIJ6	67.97

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 11. Enrichment computed across 5 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
HSF1-dependent transactivation	2	211.5×	3e-04	HSPB1, HSPB8
Attenuation phase	1	135.9×	0.022	HSPB1
HSF1 activation	1	126.9×	0.022	HSPB1
EGR2 and SOX10-mediated initiation of Schwann cell myelination	1	122.8×	0.022	MPZ
AUF1 (hnRNP D0) binds and destabilizes mRNA	1	82.8×	0.026	HSPB1
Extra-nuclear estrogen signaling	1	56.8×	0.027	HSPB1
Regulation of HSF1-mediated heat shock response	1	46.4×	0.027	HSPB1
VEGFA-VEGFR2 Pathway	1	46.4×	0.027	HSPB1
MAPK6/MAPK4 signaling	1	45.3×	0.027	HSPB1
Nervous system development	1	14.3×	0.075	MPZ
Developmental Biology	1	4.8×	0.194	MPZ

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
response to unfolded protein	2	120.4×	0.004	HSPB1, HSPB3
negative regulation of protein kinase C signaling	1	3370.4×	0.005	HSPB1
cell aggregation	1	1685.2×	0.007	MPZ
positive regulation of aggrephagy	1	561.7×	0.013	HSPB8
positive regulation of T cell mediated immune response to tumor cell	1	481.5×	0.013	FBXO38
anterograde axonal protein transport	1	421.3×	0.013	HSPB1
intestinal epithelial structure maintenance	1	374.5×	0.013	HSPB1
regulation of protein phosphorylation	1	224.7×	0.016	HSPB1
obsolete cell-cell adhesion via plasma-membrane adhesion molecules	1	224.7×	0.016	MPZ
cellular response to unfolded protein	1	198.3×	0.016	HSPB8
positive regulation of endothelial cell chemotaxis	1	198.3×	0.016	HSPB1
negative regulation of oxidative stress-induced intrinsic apoptotic signaling pathway	1	187.2×	0.016	HSPB1
protein refolding	1	124.8×	0.022	HSPB1
cellular response to vascular endothelial growth factor stimulus	1	112.3×	0.022	HSPB1
regulation of canonical NF-kappaB signal transduction	1	96.3×	0.022	HSPB1
vascular endothelial growth factor receptor signaling pathway	1	96.3×	0.022	HSPB1
regulation of translational initiation	1	93.6×	0.022	HSPB1
positive regulation of T cell activation	1	88.7×	0.022	FBXO38
response to heat	1	84.3×	0.022	HSPB1
positive regulation of blood vessel endothelial cell migration	1	78.4×	0.022	HSPB1
SCF-dependent proteasomal ubiquitin-dependent protein catabolic process	1	74.9×	0.022	FBXO38
platelet aggregation	1	67.4×	0.023	HSPB1
positive regulation of interleukin-1 beta production	1	51.9×	0.029	HSPB1
myelination	1	50.3×	0.029	MPZ
regulation of autophagy	1	48.1×	0.029	HSPB1
protein K48-linked ubiquitination	1	33.7×	0.039	FBXO38
positive regulation of tumor necrosis factor production	1	30.6×	0.042	HSPB1
response to virus	1	28.8×	0.043	HSPB1
positive regulation of neuron projection development	1	27.4×	0.043	FBXO38
positive regulation of angiogenesis	1	23.1×	0.050	HSPB1

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
HSPB1	1	2
FBXO38	0	0
HSPB8	0	0
HSPB3	0	0
MPZ	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
DORAMAPIMOD	2	HSPB1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
HSPB1	70	Binding:70

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)
DORAMAPIMOD	2	HSPB1

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	HSPB1
C	Druggable family + PDB, no drug	1	MPZ
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	3	FBXO38, HSPB8, HSPB3

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)
FBXO38	0	—
HSPB8	0	—
HSPB3	0	—
MPZ	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.