Demyelinating hereditary motor and sensory neuropathy

Summary

Demyelinating hereditary motor and sensory neuropathy (MONDO:0018776) is a disease caused by variants in MTMR2 and FBLN5, with 2 cohort genes.

At a glance

• Causal genes: MTMR2 (GenCC Definitive), FBLN5 (GenCC Strong)
• Cohort genes: 2

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	demyelinating hereditary motor and sensory neuropathy
Mondo ID	MONDO:0018776
Orphanet	476116
UMLS	C5680106
MedGen	1843348
GARD	0021952
Is cancer (heuristic)	no

Also known as: demyelinating hereditary motor and sensory neuropathy · demyelinating HMSN

Data availability: 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 › hereditary motor and sensory neuropathy › demyelinating hereditary motor and sensory neuropathy

Related subtypes (7): polyneuropathy-hand defect syndrome, hereditary thermosensitive neuropathy, autosomal dominant slowed nerve conduction velocity, hereditary sensorimotor neuropathy with hyperelastic skin, 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

No tiered GWAS variants or ClinVar records for this disease.

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 19 · Orphanet: 4 · 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
MTMR2	Definitive	Autosomal recessive	demyelinating hereditary motor and sensory neuropathy	5
FBLN5	Strong	Autosomal dominant	Charcot-Marie-Tooth disease, demyelinating, IIA 1H	14

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
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
MTMR2	Orphanet:99955	Charcot-Marie-Tooth disease type 4B1

Cohort genes → proteins

2 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	2

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
FBLN5	HGNC:3602	ENSG00000140092	Q9UBX5	Fibulin-5	gencc
MTMR2	HGNC:7450	ENSG00000087053	Q13614	Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR2	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
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.
MTMR2	Phosphatidylinositol-3,5-bisphosphate 3-phosphatase MTMR2	Lipid phosphatase that specifically dephosphorylates the D-3 position of phosphatidylinositol 3-phosphate and phosphatidylinositol 3,5-bisphosphate, generating phosphatidylinositol and phosphatidylinositol 5-phosphate.

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.5

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
Phosphatase	1	42.0×	0.047
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
FBLN5	Other/Unknown	no		EGF-type_Asp/Asn_hydroxyl_site, EGF, EGF-like_Ca-bd_dom
MTMR2	Phosphatase	yes	3.1.3.64	Tyr_Pase_dom, Tyr_Pase_cat, GRAM

Expression context

Cohort genes with no expression data: 0.

2 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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
ascending aorta	1
descending thoracic aorta	1
thoracic aorta	1
male germ cell	1
parotid gland	1
sperm	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
FBLN5	261	ubiquitous	marker	thoracic aorta, ascending aorta, descending thoracic aorta
MTMR2	288	ubiquitous	marker	sperm, parotid gland, male germ cell

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
FBLN5	2,301
MTMR2	1,121

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MTMR2	Q13614	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
FBLN5	Q9UBX5	83.69

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 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
Synthesis of PIPs at the ER membrane	1	1142.0×	0.009	MTMR2
Synthesis of PIPs at the late endosome membrane	1	475.8×	0.009	MTMR2
Synthesis of PIPs at the early endosome membrane	1	356.9×	0.009	MTMR2
PI Metabolism	1	178.4×	0.011	MTMR2
Elastic fibre formation	1	167.9×	0.011	FBLN5
Molecules associated with elastic fibres	1	154.3×	0.011	FBLN5
Synthesis of PIPs at the plasma membrane	1	105.7×	0.012	MTMR2
Phospholipid metabolism	1	100.2×	0.012	MTMR2
Metabolism of lipids	1	15.8×	0.069	MTMR2
Metabolism	1	5.8×	0.165	MTMR2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intramembranous bone growth	1	8426.0×	0.001	FBLN5
negative regulation of receptor catabolic process	1	8426.0×	0.001	MTMR2
regulation of phosphatidylinositol dephosphorylation	1	1404.3×	0.003	MTMR2
regulation of removal of superoxide radicals	1	1404.3×	0.003	FBLN5
secretion	1	1053.2×	0.003	FBLN5
negative regulation of myelination	1	936.2×	0.003	MTMR2
myelin assembly	1	936.2×	0.003	MTMR2
positive regulation of early endosome to late endosome transport	1	936.2×	0.003	MTMR2
elastic fiber assembly	1	766.0×	0.003	FBLN5
negative regulation of excitatory postsynaptic potential	1	648.1×	0.003	MTMR2
dendritic spine maintenance	1	648.1×	0.003	MTMR2
negative regulation of receptor internalization	1	601.9×	0.003	MTMR2
positive regulation of osteoblast proliferation	1	601.9×	0.003	FBLN5
negative regulation of endocytosis	1	468.1×	0.003	MTMR2
phosphatidylinositol dephosphorylation	1	324.1×	0.005	MTMR2
protein localization to cell surface	1	247.8×	0.006	FBLN5
phosphatidylinositol biosynthetic process	1	183.2×	0.007	MTMR2
neuron development	1	127.7×	0.010	MTMR2
negative regulation of angiogenesis	1	84.3×	0.013	FBLN5
cell-matrix adhesion	1	81.8×	0.013	FBLN5
negative regulation of transcription by RNA polymerase II	1	8.9×	0.115	FBLN5
positive regulation of transcription by RNA polymerase II	1	7.4×	0.130	FBLN5

Therapeutics

Drug target analysis

Approved (phase 4): 0 · Phase ≥3: 0 · Phased (≥1): 0 · Undrugged: 2

Druggability breadth: 0 of 2 evidence-associated genes (0%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
FBLN5	0	0
MTMR2	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
MTMR2	3.1.3.64, 3.1.3.95	phosphatidylinositol-3-phosphatase, phosphatidylinositol-3,5-bisphosphate 3-phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; 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	1	MTMR2
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	FBLN5

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
FBLN5	0	—
MTMR2	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.