early-onset Lafora body disease

Summary

early-onset Lafora body disease (MONDO:0014717) is a disease caused by PRDM8 (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: PRDM8 (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 439
• Phenotypes (HPO): 12

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		3	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

12 HPO clinical features (Orphanet curated; top 12 by frequency):

HPO ID	Term	Frequency
HP:0001336	Myoclonus	Very frequent (80-99%)
HP:0100318	Lafora bodies	Very frequent (80-99%)
HP:0000708	Atypical behavior	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001268	Mental deterioration	Occasional (5-29%)
HP:0001285	Spastic tetraparesis	Occasional (5-29%)
HP:0001289	Confusion	Occasional (5-29%)
HP:0002300	Mutism	Occasional (5-29%)
HP:0011999	Paranoia	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	early-onset Lafora body disease
Mondo ID	MONDO:0014717
OMIM	616640
Orphanet	324290
DOID	DOID:0111445
SNOMED CT	733082001
UMLS	C4225258
MedGen	907932
GARD	0017482
Is cancer (heuristic)	no

Also known as: epilepsy, progressive myoclonic, 10 · epilepsy, progressive myoclonic, type 10 · EPM10

Data availability: 439 ClinVar variants · 3 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › hereditary neurological disease › progressive myoclonus epilepsy › early-onset Lafora body disease

Related subtypes (14): Lafora disease, Unverricht-Lundborg syndrome, action myoclonus-renal failure syndrome, MERRF syndrome, familial encephalopathy with neuroserpin inclusion bodies, neuronal ceroid lipofuscinosis 8 northern epilepsy variant, progressive myoclonic epilepsy type 3, epilepsy, progressive myoclonic, 1B, progressive myoclonic epilepsy type 6, progressive myoclonic epilepsy type 7, progressive myoclonic epilepsy type 8, progressive myoclonic epilepsy type 9, epilepsy, progressive myoclonic, 11, epilepsy, progressive myoclonic, 12

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

439 retrieved; paginated sample, class counts are floors:

242 uncertain significance, 179 likely benign, 15 benign, 2 benign/likely benign, 1 pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
217865	NM_001099403.2(PRDM8):c.781T>C (p.Phe261Leu)	PRDM8	Pathogenic	no assertion criteria provided
1347224	NC_000004.11:g.(?80828583)(81124686_?)del	ANTXR2	Uncertain significance	criteria provided, single submitter
1037877	NM_001099403.2(PRDM8):c.552C>A (p.Ser184Arg)	LOC126807094	Uncertain significance	criteria provided, single submitter
1055077	NM_001099403.2(PRDM8):c.428C>T (p.Ser143Phe)	LOC126807094	Uncertain significance	criteria provided, single submitter
1060338	NM_001099403.2(PRDM8):c.269G>A (p.Arg90Gln)	LOC126807094	Uncertain significance	criteria provided, multiple submitters, no conflicts
1345373	NM_001099403.2(PRDM8):c.488G>A (p.Arg163His)	LOC126807094	Uncertain significance	criteria provided, single submitter
1353013	NM_001099403.2(PRDM8):c.441_444del (p.Asn147fs)	LOC126807094	Uncertain significance	criteria provided, single submitter
1397193	NM_001099403.2(PRDM8):c.260T>C (p.Met87Thr)	LOC126807094	Uncertain significance	criteria provided, single submitter
1405204	NM_001099403.2(PRDM8):c.250G>A (p.Glu84Lys)	LOC126807094	Uncertain significance	criteria provided, multiple submitters, no conflicts
1435918	NM_001099403.2(PRDM8):c.296A>G (p.Glu99Gly)	LOC126807094	Uncertain significance	criteria provided, single submitter
1440154	NM_001099403.2(PRDM8):c.232G>A (p.Ala78Thr)	LOC126807094	Uncertain significance	criteria provided, single submitter
1497184	NM_001099403.2(PRDM8):c.328G>A (p.Gly110Arg)	LOC126807094	Uncertain significance	criteria provided, single submitter
1502850	NM_001099403.2(PRDM8):c.532T>C (p.Cys178Arg)	LOC126807094	Uncertain significance	criteria provided, single submitter
1514150	NM_001099403.2(PRDM8):c.224A>T (p.Asp75Val)	LOC126807094	Uncertain significance	criteria provided, single submitter
1941677	NM_001099403.2(PRDM8):c.331C>G (p.Gln111Glu)	LOC126807094	Uncertain significance	criteria provided, single submitter
2002239	NM_001099403.2(PRDM8):c.502T>C (p.Phe168Leu)	LOC126807094	Uncertain significance	criteria provided, single submitter
2015490	NM_001099403.2(PRDM8):c.259A>G (p.Met87Val)	LOC126807094	Uncertain significance	criteria provided, single submitter
2107873	NM_001099403.2(PRDM8):c.424C>T (p.Pro142Ser)	LOC126807094	Uncertain significance	criteria provided, multiple submitters, no conflicts
2886100	NM_001099403.2(PRDM8):c.556G>C (p.Asp186His)	LOC126807094	Uncertain significance	criteria provided, multiple submitters, no conflicts
4777782	NM_001099403.2(PRDM8):c.473T>C (p.Leu158Pro)	LOC126807094	Uncertain significance	criteria provided, single submitter
542336	NM_001099403.2(PRDM8):c.329G>C (p.Gly110Ala)	LOC126807094	Uncertain significance	criteria provided, multiple submitters, no conflicts
565549	NM_001099403.2(PRDM8):c.543A>T (p.Arg181Ser)	LOC126807094	Uncertain significance	criteria provided, single submitter
574303	NM_001099403.2(PRDM8):c.506C>T (p.Pro169Leu)	LOC126807094	Uncertain significance	criteria provided, single submitter
839945	NM_001099403.2(PRDM8):c.378A>T (p.Leu126Phe)	LOC126807094	Uncertain significance	criteria provided, single submitter
937942	NM_001099403.2(PRDM8):c.373G>A (p.Glu125Lys)	LOC126807094	Uncertain significance	criteria provided, single submitter
942442	NM_001099403.2(PRDM8):c.404C>T (p.Thr135Ile)	LOC126807094	Uncertain significance	criteria provided, single submitter
978527	NM_001099403.2(PRDM8):c.560T>C (p.Ile187Thr)	LOC126807094	Uncertain significance	criteria provided, single submitter
1007878	NM_001099403.2(PRDM8):c.973G>A (p.Gly325Ser)	LOC129992744	Uncertain significance	criteria provided, multiple submitters, no conflicts
1019467	NM_001099403.2(PRDM8):c.983G>C (p.Gly328Ala)	LOC129992744	Uncertain significance	criteria provided, multiple submitters, no conflicts
1434308	NM_001099403.2(PRDM8):c.956A>C (p.Glu319Ala)	LOC129992744	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 3 · 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
PRDM8	Strong	Autosomal recessive	early-onset Lafora body disease	3

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
PRDM8	Orphanet:324290	PRDM8-related progressive myoclonus epilepsy
ANTXR2	Orphanet:2028	Juvenile hyaline fibromatosis
ANTXR2	Orphanet:2176	Infantile systemic hyalinosis

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
PRDM8	HGNC:13993	ENSG00000152784	Q9NQV8	PR domain zinc finger protein 8	gencc,clinvar
ANTXR2	HGNC:21732	ENSG00000163297	P58335	Anthrax toxin receptor 2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
PRDM8	PR domain zinc finger protein 8	Probable histone methyltransferase, preferentially acting on ‘Lys-9’ of histone H3.
ANTXR2	Anthrax toxin receptor 2	Necessary for cellular interactions with laminin and the extracellular matrix.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 1 · 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
Transcription factor	1	4.1×	0.455
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
PRDM8	Transcription factor	no		SET_dom, Znf_C2H2_type, Znf_C2H2_sf
ANTXR2	Other/Unknown	no		VWF_A, Anthrax_toxin_rcpt_C, Anthrax_toxin_rcpt_extracel

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
mucosa of stomach	2
cortical plate	1
ganglionic eminence	1
decidua	1
smooth muscle tissue	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
PRDM8	159	ubiquitous	marker	cortical plate, ganglionic eminence, mucosa of stomach
ANTXR2	243	ubiquitous	marker	mucosa of stomach, decidua, smooth muscle tissue

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ANTXR2	1,270
PRDM8	794

Intra-cohort edges

A	B	Sources
ANTXR2	PRDM8	string_interaction

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ANTXR2	P58335	14

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRDM8	Q9NQV8	55.64

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
Regulation of CDH11 gene transcription	1	519.1×	0.002	PRDM8
Uptake and function of anthrax toxins	1	475.8×	0.002	ANTXR2

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
corpus callosum morphogenesis	1	1203.7×	0.003	PRDM8
corticospinal tract morphogenesis	1	1203.7×	0.003	PRDM8
uterus development	1	401.2×	0.007	ANTXR2
oligodendrocyte development	1	300.9×	0.007	PRDM8
collagen fibril organization	1	112.3×	0.013	ANTXR2
single fertilization	1	91.6×	0.013	ANTXR2
methylation	1	85.1×	0.013	PRDM8
regulation of DNA-templated transcription	1	15.8×	0.062	PRDM8

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 2 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
PRDM8	0	0
ANTXR2	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
ANTXR2	3	Binding:3
PRDM8	1	Binding:1

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	0
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	PRDM8, ANTXR2

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)
PRDM8	1	—
ANTXR2	3	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.