Lafora disease

Summary

Lafora disease (MONDO:0009697) is a disease caused by variants in EPM2A and NHLRC1, with 2 cohort genes and 4 clinical trials. Top therapeutic interventions include clervonafusp alfa.

At a glance

• Prevalence: 1-9 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal genes: EPM2A (GenCC Definitive), NHLRC1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 395
• Phenotypes (HPO): 35
• Clinical trials: 4

Clinical features

Epidemiology

Prevalence records

4 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		300	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.02	Worldwide	Validated
Point prevalence	1-9 / 1 000 000	0.1	France	Validated
Point prevalence	1-9 / 1 000 000		Europe	Not yet validated

Signs & symptoms

Clinical features (HPO)

35 HPO clinical features (Orphanet curated; top 35 by frequency):

HPO ID	Term	Frequency
HP:0100318	Lafora bodies	Obligate (100%)
HP:0001250	Seizure	Very frequent (80-99%)
HP:0000712	Emotional lability	Frequent (30-79%)
HP:0000716	Depression	Frequent (30-79%)
HP:0000726	Dementia	Frequent (30-79%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001257	Spasticity	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001268	Mental deterioration	Frequent (30-79%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0001289	Confusion	Frequent (30-79%)
HP:0001312	Giant somatosensory evoked potentials	Frequent (30-79%)
HP:0002100	Recurrent aspiration pneumonia	Frequent (30-79%)
HP:0002123	Generalized myoclonic seizure	Frequent (30-79%)
HP:0002133	Status epilepticus	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002367	Visual hallucinations	Frequent (30-79%)
HP:0002521	Hypsarrhythmia	Frequent (30-79%)
HP:0002540	Inability to walk	Frequent (30-79%)
HP:0025357	Erratic myoclonus	Frequent (30-79%)
HP:0040288	Nasogastric tube feeding	Frequent (30-79%)
HP:0001336	Myoclonus	Occasional (5-29%)
HP:0001399	Hepatic failure	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002121	Generalized non-motor (absence) seizure	Occasional (5-29%)
HP:0002360	Sleep abnormality	Occasional (5-29%)
HP:0002384	Focal impaired awareness seizure	Occasional (5-29%)
HP:0007270	Atypical absence seizure	Occasional (5-29%)
HP:0007334	Bilateral tonic-clonic seizure with focal onset	Occasional (5-29%)
HP:0007359	Focal-onset seizure	Occasional (5-29%)
HP:0007537	Severe photosensitivity	Occasional (5-29%)
HP:0010819	Atonic seizure	Occasional (5-29%)
HP:0011165	Focal sensory seizure with visual features	Occasional (5-29%)
HP:0012444	Brain atrophy	Occasional (5-29%)
HP:0031358	Vegetative state	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Lafora disease
Mondo ID	MONDO:0009697
MeSH	D020192
OMIM	254780
Orphanet	501
DOID	DOID:3534
NCIT	C84804
SNOMED CT	230425004
UMLS	C0751783
MedGen	155631
GARD	0008214
MedDRA	10054030
NORD	143373
Is cancer (heuristic)	no

Also known as: epilepsy progressive myoclonic 2 · epilepsy, progressive myoclonic 2A (Lafora) · epilepsy, progressive myoclonic 2B (Lafora) · EPM2 · Lafora body disorder · Lafora disease · myoclonic epilepsy of Lafora · PME type 2 · progressive myoclonic epilepsy type 2 · progressive myoclonus epilepsy type 2

Data availability: 395 ClinVar variants · 9 GenCC gene-disease records · 2 cell lines.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn carbohydrate metabolic disorder › disorder of glycogen metabolism › Lafora disease

Related subtypes (23): glycogen storage disease I, glycogen storage disease due to GLUT2 deficiency, glycogen storage disease II, glycogen storage disease III, glycogen storage disease due to glycogen branching enzyme deficiency, glycogen storage disease V, glycogen storage disease VI, glycogen storage disease VII, glycogen storage disorder due to hepatic glycogen synthase deficiency, glycogen storage disease due to phosphoglycerate mutase deficiency, lethal congenital glycogen storage disease of heart, Danon disease, glycogen storage disease IXd, glycogen storage disease due to phosphoglycerate kinase 1 deficiency, glycogen storage disease due to muscle and heart glycogen synthase deficiency, glycogen storage disease due to muscle beta-enolase deficiency, glycogen storage disease due to lactate dehydrogenase M-subunit deficiency, polyglucosan body myopathy 1 with or without immunodeficiency, glycogen storage disease due to lactate dehydrogenase deficiency, autoinflammatory syndrome with pyogenic bacterial infection and amylopectinosis, glycogen storage disease due to liver phosphorylase kinase deficiency, GYG1-related disorder of glycogen metabolism, glycogen storage disease IX

Subtypes (2): myoclonic epilepsy of Lafora 2, myoclonic epilepsy of Lafora 1

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

395 retrieved; paginated sample, class counts are floors:

205 uncertain significance, 78 likely benign, 36 pathogenic, 26 conflicting classifications of pathogenicity, 16 pathogenic/likely pathogenic, 15 likely pathogenic, 12 benign, 7 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1047431	NM_005670.4(EPM2A):c.794A>G (p.His265Arg)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068477	NM_005670.4(EPM2A):c.302-2A>G	EPM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1075527	NM_005670.4(EPM2A):c.108_139del (p.Ala37fs)	EPM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1393093	NM_005670.4(EPM2A):c.302-1G>C	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1451802	NM_005670.4(EPM2A):c.258C>G (p.Tyr86Ter)	EPM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
1510680	NM_005670.4(EPM2A):c.301+1G>T	EPM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
205431	NM_005670.4(EPM2A):c.166G>T (p.Glu56Ter)	EPM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
2431059	NM_005670.4(EPM2A):c.179G>A (p.Trp60Ter)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3098	NM_005670.4(EPM2A):c.721C>T (p.Arg241Ter)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3099	NM_005670.4(EPM2A):c.835G>A (p.Gly279Ser)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3100	NM_005670.4(EPM2A):c.322C>T (p.Arg108Cys)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3101	NM_005670.4(EPM2A):c.335dup (p.Tyr112Ter)	EPM2A	Pathogenic	criteria provided, single submitter
3102	NM_005670.4(EPM2A):c.512G>A (p.Arg171His)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3107	NM_005670.4(EPM2A):c.94T>G (p.Trp32Gly)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3776856	NM_005670.4(EPM2A):c.336C>A (p.Tyr112Ter)	EPM2A	Pathogenic	criteria provided, single submitter
3776900	NM_005670.4(EPM2A):c.259A>T (p.Lys87Ter)	EPM2A	Pathogenic	criteria provided, single submitter
3776909	NM_005670.4(EPM2A):c.243_246del (p.Asp82fs)	EPM2A	Pathogenic	criteria provided, single submitter
381553	NM_005670.4(EPM2A):c.495G>A (p.Trp165Ter)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
419335	NM_005670.4(EPM2A):c.163C>T (p.Gln55Ter)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
834981	NM_005670.4(EPM2A):c.835G>T (p.Gly279Cys)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
872146	NM_005670.4(EPM2A):c.269_275del (p.Lys90fs)	EPM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
954222	NM_005670.4(EPM2A):c.363_364dup (p.Tyr122fs)	EPM2A	Pathogenic	criteria provided, multiple submitters, no conflicts
956069	NM_005670.4(EPM2A):c.118del (p.Arg39_Leu40insTer)	EPM2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1029356	NM_198586.3(NHLRC1):c.368G>A (p.Trp123Ter)	NHLRC1	Pathogenic	criteria provided, single submitter
1069688	NM_198586.3(NHLRC1):c.799del (p.Val267fs)	NHLRC1	Pathogenic	criteria provided, single submitter
1071786	NM_198586.3(NHLRC1):c.670_673del (p.Thr224fs)	NHLRC1	Pathogenic	criteria provided, single submitter
1299569	NM_198586.3(NHLRC1):c.583del (p.Asp195fs)	NHLRC1	Pathogenic	criteria provided, single submitter
1412922	NM_198586.3(NHLRC1):c.37_38insTC (p.His13fs)	NHLRC1	Pathogenic	criteria provided, single submitter
1452637	NM_198586.3(NHLRC1):c.865_880del (p.Gly288_Val289insTer)	NHLRC1	Pathogenic	criteria provided, single submitter
1453372	NM_198586.3(NHLRC1):c.799dup (p.Val267fs)	NHLRC1	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 2 · 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
EPM2A	Definitive	Autosomal recessive	Lafora disease	5
NHLRC1	Definitive	Autosomal recessive	Lafora disease	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
NHLRC1	Orphanet:501	Lafora disease
EPM2A	Orphanet:501	Lafora disease

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
NHLRC1	HGNC:21576	ENSG00000187566	Q6VVB1	E3 ubiquitin-protein ligase NHLRC1	gencc,clinvar
EPM2A	HGNC:3413	ENSG00000112425	B3EWF7	Laforin, isoform 9	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
NHLRC1	E3 ubiquitin-protein ligase NHLRC1	E3 ubiquitin-protein ligase.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 0 · 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
Transcription factor	1	4.1×	0.228

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
NHLRC1	Transcription factor	no		NHL_repeat, Znf_RING, 6-blade_b-propeller_TolB-like
EPM2A	Phosphatase	yes	3.1.3.16	Dual-sp_phosphatase_cat-dom, Tyr_Pase_dom, CBM20

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)	2
unknown	0

Top tissues across cohort

Tissue	Cohort genes
hindlimb stylopod muscle	2
islet of Langerhans	1
prefrontal cortex	1
biceps brachii	1
skeletal muscle tissue of rectus abdominis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
NHLRC1	129	broad	yes	prefrontal cortex, islet of Langerhans, hindlimb stylopod muscle
EPM2A	281	ubiquitous	marker	skeletal muscle tissue of rectus abdominis, biceps brachii, hindlimb stylopod muscle

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
NHLRC1	939
EPM2A	4

Intra-cohort edges

A	B	Sources
EPM2A	NHLRC1	biogrid_interaction, intact

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EPM2A	B3EWF7	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
NHLRC1	Q6VVB1	85.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 2. 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
Myoclonic epilepsy of Lafora	2	1268.9×	1e-06	NHLRC1, EPM2A
Glycogen synthesis	2	815.7×	1e-06	NHLRC1, EPM2A

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
glycogen biosynthetic process	2	936.2×	3e-05	NHLRC1, EPM2A
regulation of protein localization to plasma membrane	2	648.1×	4e-05	NHLRC1, EPM2A
negative regulation of phosphatase activity	1	2808.7×	0.002	EPM2A
negative regulation of dephosphorylation	1	2106.5×	0.002	EPM2A
habituation	1	2106.5×	0.002	EPM2A
proteasome-mediated ubiquitin-dependent protein catabolic process	2	52.2×	0.002	NHLRC1, EPM2A
regulation of protein import into nucleus	1	1685.2×	0.003	EPM2A
carbohydrate phosphorylation	1	1053.2×	0.004	EPM2A
glial cell proliferation	1	443.5×	0.006	EPM2A
regulation of protein ubiquitination	1	443.5×	0.006	EPM2A
peptidyl-tyrosine dephosphorylation	1	443.5×	0.006	EPM2A
L-glutamate transmembrane transport	1	401.2×	0.006	EPM2A
regulation of proteasomal protein catabolic process	1	383.0×	0.006	EPM2A
dephosphorylation	1	337.0×	0.007	EPM2A
negative regulation of TOR signaling	1	280.9×	0.007	EPM2A
glycogen metabolic process	1	263.3×	0.007	EPM2A
positive regulation of macroautophagy	1	263.3×	0.007	EPM2A
negative regulation of cell cycle	1	145.3×	0.012	EPM2A
autophagosome assembly	1	112.3×	0.013	EPM2A
regulation of cell growth	1	110.9×	0.013	EPM2A
protein dephosphorylation	1	110.9×	0.013	EPM2A
positive regulation of protein ubiquitination	1	106.7×	0.013	NHLRC1
calcium ion transport	1	90.6×	0.015	EPM2A
response to endoplasmic reticulum stress	1	83.4×	0.015	NHLRC1
mitochondrion organization	1	75.9×	0.016	EPM2A
protein polyubiquitination	1	57.7×	0.021	NHLRC1
autophagy	1	55.1×	0.021	NHLRC1
Wnt signaling pathway	1	49.9×	0.022	EPM2A
regulation of gene expression	1	41.7×	0.025	NHLRC1
ubiquitin-dependent protein catabolic process	1	37.1×	0.028	NHLRC1

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
NHLRC1	0	0
EPM2A	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
EPM2A	3.1.3.16	protein-serine/threonine 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	EPM2A
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	NHLRC1

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)
NHLRC1	0	—
EPM2A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 4.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	3
PHASE1/PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06609889	PHASE1/PHASE2	RECRUITING	A Safety and Efficacy of Intrathecally Administered ION283 in Patients With Lafora Disease
NCT05930223	Not specified	AVAILABLE	Intravenous VAL-1221 Lafora Expanded Access Protocol
NCT00007124	Not specified	COMPLETED	Ketogenic Diet in Lafora Disease
NCT03876522	Not specified	COMPLETED	Natural History and Functional Status Study of Patients With Lafora Disease

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
CLERVONAFUSP ALFA	2	1