GNE myopathy

Summary

GNE myopathy (MONDO:0011603) is a disease caused by GNE (GenCC Definitive), with 1 cohort gene and 15 clinical trials. Top therapeutic interventions include n-acetylmannosamine.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide) [Orphanet-validated]
• Causal gene: GNE (GenCC Definitive)
• Cohort genes: 1
• ClinVar variants: 1,025
• Phenotypes (HPO): 28
• Clinical trials: 15

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Worldwide	Validated
Point prevalence	6-9 / 10 000	66.7	Specific population	Validated

Signs & symptoms

Clinical features (HPO)

28 HPO clinical features (Orphanet curated; top 28 by frequency):

HPO ID	Term	Frequency
HP:0003805	Rimmed vacuoles	Very frequent (80-99%)
HP:0007340	Lower limb muscle weakness	Very frequent (80-99%)
HP:0008180	Mildly elevated creatine kinase	Very frequent (80-99%)
HP:0008963	Tibialis muscle weakness	Very frequent (80-99%)
HP:0009027	Foot dorsiflexor weakness	Very frequent (80-99%)
HP:0012548	Fatty replacement of skeletal muscle	Very frequent (80-99%)
HP:0100299	Muscle fiber inclusion bodies	Very frequent (80-99%)
HP:0000821	Hypothyroidism	Frequent (30-79%)
HP:0003376	Steppage gait	Frequent (30-79%)
HP:0003438	Absent Achilles reflex	Frequent (30-79%)
HP:0003458	EMG: myopathic abnormalities	Frequent (30-79%)
HP:0003547	Shoulder girdle muscle weakness	Frequent (30-79%)
HP:0003557	Increased variability in muscle fiber diameter	Frequent (30-79%)
HP:0006251	Limited wrist extension	Frequent (30-79%)
HP:0006467	Limited shoulder movement	Frequent (30-79%)
HP:0012515	Hip flexor weakness	Frequent (30-79%)
HP:0030007	EMG: positive sharp waves	Frequent (30-79%)
HP:0100284	EMG: myotonic discharges	Frequent (30-79%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001436	Abnormality of the foot musculature	Occasional (5-29%)
HP:0003691	Scapular winging	Occasional (5-29%)
HP:0003724	Shoulder girdle muscle atrophy	Occasional (5-29%)
HP:0007210	Lower limb amyotrophy	Occasional (5-29%)
HP:0010628	Facial palsy	Occasional (5-29%)
HP:0040047	Abnormality of the right hemidiaphragm	Occasional (5-29%)
HP:0003731	Quadriceps muscle weakness	Excluded (0%)
HP:0001638	Cardiomyopathy	Very rare (<1-4%)
HP:0009077	Weakness of long finger extensor muscles	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	GNE myopathy
Mondo ID	MONDO:0011603
OMIM	605820
Orphanet	602
DOID	DOID:0080718
SNOMED CT	702382000
UMLS	C1853926
MedGen	381298
GARD	0009493
NORD	2011
Is cancer (heuristic)	no

Also known as: distal myopathy with rimmed vacuoles · distal myopathy, Nonaka type · DMRV · hereditary inclusion body myopathy type 2 · HIBM2 · IBM2 · inclusion body myopathy 2, autosomal recessive · inclusion body myopathy autosomal recessive · inclusion body myopathy type 2 · inclusion body myopathy, autosomal recessive · inclusion body myopathy, quadriceps-sparing · NM · Nonaka myopathy · QSM · quadriceps sparing myopathy · quadriceps-sparing myopathy · rimmed vacuole myopathy

Data availability: 1,025 ClinVar variants · 5 GenCC gene-disease records · 14 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › musculoskeletal system disorder › muscle tissue disorder › skeletal muscle disorder › myopathy › myositis disease › inclusion body myositis › GNE myopathy

Related subtypes (1): myopathy, proximal, and ophthalmoplegia

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:

298 likely benign, 174 uncertain significance, 39 pathogenic, 37 conflicting classifications of pathogenicity, 28 likely pathogenic, 18 pathogenic/likely pathogenic, 3 benign, 3 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1068026	NM_005476.7(GNE):c.2005_2011del (p.Gly669fs)	GNE	Pathogenic	criteria provided, single submitter
1069453	NM_001128227.3(GNE):c.55_62del (p.Glu18_Leu19insTer)	GNE	Pathogenic	criteria provided, single submitter
1070560	NM_005476.7(GNE):c.1690del (p.Ala564fs)	GNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1072426	NM_005476.7(GNE):c.1816+5G>A	GNE	Pathogenic	criteria provided, multiple submitters, no conflicts
1075047	NM_005476.7(GNE):c.221_222del (p.Thr74fs)	GNE	Pathogenic	criteria provided, multiple submitters, no conflicts
1323024	NM_005476.7(GNE):c.1220dup (p.Ser408fs)	GNE	Pathogenic	criteria provided, multiple submitters, no conflicts
1323025	NM_005476.7(GNE):c.723_727del (p.Ile241_Ser242insTer)	GNE	Pathogenic	criteria provided, multiple submitters, no conflicts
1371995	NM_005476.7(GNE):c.454_616+70delinsTAG	GNE	Pathogenic	criteria provided, single submitter
1377078	NM_005476.7(GNE):c.1789C>T (p.Gln597Ter)	GNE	Pathogenic	criteria provided, single submitter
1388859	NM_005476.7(GNE):c.1018C>T (p.Gln340Ter)	GNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1412885	NM_005476.7(GNE):c.1112del (p.Ile370_Leu371insTer)	GNE	Pathogenic	criteria provided, single submitter
1413067	NM_005476.7(GNE):c.997dup (p.His333fs)	GNE	Pathogenic	criteria provided, single submitter
1428290	NM_005476.7(GNE):c.952_953del (p.Leu318fs)	GNE	Pathogenic	criteria provided, single submitter
1448509	NM_005476.7(GNE):c.174_177dup (p.Met60fs)	GNE	Pathogenic	criteria provided, single submitter
1451866	NM_005476.7(GNE):c.1643del (p.Gly548fs)	GNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1452395	NM_005476.7(GNE):c.1501_1529del (p.Arg501fs)	GNE	Pathogenic	criteria provided, single submitter
1453995	NM_005476.7(GNE):c.1048C>T (p.Gln350Ter)	GNE	Pathogenic	criteria provided, single submitter
1458582	NC_000009.11:g.(?36227235)(36227465_?)del	GNE	Pathogenic	criteria provided, single submitter
162151	NM_005476.7(GNE):c.711G>A (p.Leu237=)	GNE	Pathogenic	criteria provided, single submitter
188796	NM_005476.7(GNE):c.612G>A (p.Trp204Ter)	GNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188847	NM_005476.7(GNE):c.829C>T (p.Arg277Cys)	GNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
188882	NM_005476.7(GNE):c.1760T>C (p.Ile587Thr)	GNE	Pathogenic	criteria provided, multiple submitters, no conflicts
188916	NM_005476.7(GNE):c.1306C>T (p.Gln436Ter)	GNE	Pathogenic	criteria provided, multiple submitters, no conflicts
189156	NM_005476.7(GNE):c.386G>A (p.Arg129Gln)	GNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
197184	NM_005476.7(GNE):c.736C>T (p.Arg246Trp)	GNE	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2014927	NM_005476.7(GNE):c.798del (p.Lys267fs)	GNE	Pathogenic	criteria provided, single submitter
2018618	NM_005476.7(GNE):c.1139_1140insTAGCCTATAATTTAACTTTGACAAAGTTATGAAATGGTTTTTCTAATACCTTTTTGAAAAAGTCATGGAGGCCATGGGGTTGGCTTGAAACCAGCTTTGGGGGGTTCGATTCCTTCCTTTTTTGTCTAGATTTTATGTATACGGGTTCTTCGAATGTGTGGTTCA (p.Gln380delinsHisSerLeuTer)	GNE	Pathogenic	criteria provided, single submitter
2021712	NM_005476.7(GNE):c.1926_1927insCGGCCCAGAGCATCCTA (p.Arg643_Thr644insProArgAlaSerTer)	GNE	Pathogenic	criteria provided, single submitter
2108109	NM_005476.7(GNE):c.2135del (p.Met712fs)	GNE	Pathogenic	criteria provided, single submitter
2121685	NM_001128227.3(GNE):c.22C>T (p.Gln8Ter)	GNE	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 3 · 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
GNE	Definitive	Autosomal recessive	GNE myopathy	13

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
GNE	Orphanet:3166	Sialuria
GNE	Orphanet:438207	Severe autosomal recessive macrothrombocytopenia
GNE	Orphanet:602	GNE myopathy

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
GNE	HGNC:23657	ENSG00000159921	Q9Y223	Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
GNE	Bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase	Bifunctional enzyme that possesses both UDP-N-acetylglucosamine 2-epimerase and N-acetylmannosamine kinase activities, and serves as the initiator of the biosynthetic pathway leading to the production of N-acetylneuraminic acid (NeuAc), a…

Protein-family classification

Druggable: 1 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
GNE	Enzyme (other)	yes	2.7.1.60	ROK, UDP_GlcNAc_Epimerase_2_dom, UDP-GlcNAc_Epase

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
colonic mucosa	1
mucosa of sigmoid colon	1
nasal cavity epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
GNE	286	ubiquitous	marker	mucosa of sigmoid colon, colonic mucosa, nasal cavity epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
GNE	2,210

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
GNE	Q9Y223	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. Enrichment computed across 1 evidence-associated genes (1 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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Defective GNE causes sialuria, NK and IBM2	1	11420.0×	2e-04	GNE
Sialic acid metabolism	1	326.3×	0.003	GNE

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
N-acetylglucosamine biosynthetic process	1	8426.0×	4e-04	GNE
N-acetylneuraminate biosynthetic process	1	5617.3×	4e-04	GNE
UDP-N-acetylglucosamine metabolic process	1	2808.7×	4e-04	GNE
CMP-N-acetylneuraminate biosynthetic process	1	2808.7×	4e-04	GNE

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 evidence-associated genes (100%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GNE	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
GNE	1	Binding:1

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
GNE	2.7.1.60, 3.2.1.183, 5.1.3.14	N-acylmannosamine kinase, UDP-N-acetylglucosamine 2-epimerase (hydrolysing), UDP-N-acetylglucosamine 2-epimerase (non-hydrolysing)

Pharmacogenomics

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

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
GNE	1	—

Clinical trials & evidence

Clinical trials

Clinical trials: 15.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE2	5
Not specified	4
PHASE3	3
PHASE1	2
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT02377921	PHASE3	COMPLETED	Phase 3 Randomized, Double-Blind, Placebo-Controlled Study to Evaluate Sialic Acid in Patients With Glucosamine (UDP-N-acetyl)-2-epimerase Myopathy (GNEM) or Hereditary Inclusion Body Myopathy (HIBM)
NCT02736188	PHASE3	TERMINATED	Study to Evaluate the Safety and Efficacy of Aceneuramic Acid Extended-Release (Ace-ER) Tablets in Patients With Glucosamine (UDP-N-acetyl)-2-epimerase Myopathy (GNEM) or Hereditary Inclusion Body Myopathy (HIBM)
NCT04671472	PHASE3	COMPLETED	Efficacy Confirmation Study of NPC-09
NCT04231266	PHASE2	ACTIVE_NOT_RECRUITING	Multi-Center Study of ManNAc for GNE Myopathy
NCT07511556	PHASE1/PHASE2	NOT_YET_RECRUITING	First-in-human Study of UX016 in GNEM
NCT01517880	PHASE2	COMPLETED	A Phase 2 Study to Evaluate the Dose and Pharmacodynamic Efficacy of Sialic Acid-Extended Release (SA-ER) Tablets in Patients With GNE Myopathy or Hereditary Inclusion Body Myopathy
NCT01830972	PHASE2	COMPLETED	An Open Label Phase 2 Extension Study of Higher Dose Sialic Acid-Extended Release (SA-ER) Tablets and Sialic Acid-Immediate Release (SA-IR) Capsules in Patients With Glucosamine (UDP-N-acetyl)-2-Epimerase (GNE) Myopathy
NCT02346461	PHASE2	COMPLETED	An Open Label Phase 2 Study of ManNAc in Subjects With GNE Myopathy
NCT02731690	PHASE2	TERMINATED	A Study to Evaluate the Safety of Aceneuramic Acid Extended Release (Ace-ER; UX001) Tablets in Glucosamine (UDP-N-acetyl)-2-Epimerase (GNE) Myopathy (GNEM) (Also Known as Hereditary Inclusion Body Myopathy [HIBM]) Patients With Severe Ambulatory Impairment
NCT01236898	PHASE1	COMPLETED	Pharmacokinetic Study on N-acetylneuraminic Acid
NCT01634750	PHASE1	COMPLETED	Phase I Clinical Trial of ManNAc in Patients With GNE Myopathy or Hereditary Inclusion Body Myopathy (HIBM)
NCT01417533	Not specified	COMPLETED	A Natural History Study of Patients With GNE Myopathy and GNE-Related Diseases
NCT01784679	Not specified	COMPLETED	GNE-Myopathy Disease Monitoring Program (GNEM-DMP): A Registry and Prospective Observational Natural History Study to Assess GNE Myopathy or Hereditary Inclusion Body Myopathy (HIBM)
NCT01902940	Not specified	COMPLETED	Natural History in CCFDN and IBM Syndromes
NCT04009226	Not specified	UNKNOWN	International GNE Myopathy Patient Registry

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
N-ACETYLMANNOSAMINE	2	3