Unverricht-Lundborg syndrome

Summary

Unverricht-Lundborg syndrome (MONDO:0009698) is a disease caused by CSTB (GenCC Definitive), with 3 cohort genes and 5 clinical trials. Top therapeutic interventions include ropinirole and brivaracetam.

At a glance

• Prevalence: 1-9 / 100 000 (Finland) [Orphanet-validated]
• Causal gene: CSTB (GenCC Definitive)
• Cohort genes: 3
• ClinVar variants: 45
• Phenotypes (HPO): 10
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	2	Finland	Validated
Prevalence at birth	1-9 / 100 000	5	Finland	Validated

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0001336	Myoclonus	Very frequent (80-99%)
HP:0002070	Limb ataxia	Very frequent (80-99%)
HP:0002392	EEG with polyspike wave complexes	Very frequent (80-99%)
HP:0007000	Morning myoclonic jerks	Very frequent (80-99%)
HP:0001251	Ataxia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0002080	Intention tremor	Frequent (30-79%)
HP:0000726	Dementia	Occasional (5-29%)
HP:0000992	Cutaneous photosensitivity	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	Unverricht-Lundborg syndrome
Mondo ID	MONDO:0009698
MeSH	D020194
OMIM	254800
Orphanet	308
DOID	DOID:0111452, DOID:3535
SNOMED CT	230423006
UMLS	C0751785
MedGen	155923
GARD	0003876
MedDRA	10054895
Is cancer (heuristic)	no

Also known as: epilepsy, progressive myoclonic 1A (Unverricht and Lundborg) · epilepsy, progressive myoclonic type 1 · epilepsy, progressive myoclonus 1 · EPM1 · myoclonus progressive epilepsy of Unverricht and Lundborg · PME type 1 · progressive myoclonic epilepsy type 1 · progressive myoclonus epilepsy Baltic myoclonic epilepsy · progressive myoclonus epilepsy type 1 · ULD · Unverricht-Lundborg disease · Unverricht-Lundborg syndrome

Data availability: 45 ClinVar variants · 5 GenCC gene-disease records · 5 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › Unverricht-Lundborg syndrome

Related subtypes (53): cerebellar ataxia, chronic tic disorder, choreatic disease, extrapyramidal and movement disease, benign shuddering attacks, transient tic disorder, essential tremor, lingual-facial-buccal dyskinesia, kuru, inherited Creutzfeldt-Jakob disease, Tourette syndrome, clonic hemifacial spasm, Huntington disease, multiple system atrophy, spinal muscular atrophy-progressive myoclonic epilepsy syndrome, benign paroxysmal tonic upgaze of childhood with ataxia, hereditary geniospasm, tremor-nystagmus-duodenal ulcer syndrome, arthrogryposis, Lafora disease, neuronal intranuclear inclusion disease, Huntington disease-like 3, brain-lung-thyroid syndrome, myoclonus, familial, proximal myopathy with extrapyramidal signs, progressive myoclonic epilepsy type 7, progressive essential tremor-speech impairment-facial dysmorphism-intellectual disability-abnormal behavior syndrome, progressive non-fluent aphasia, opsoclonus-myoclonus syndrome, isolated facial myokymia, primary orthostatic tremor, familial congenital mirror movements, neuroacanthocytosis, behavioral variant of frontotemporal dementia, frontotemporal dementia with motor neuron disease, hyperekplexia, intellectual disability-hyperkinetic movement-truncal ataxia syndrome, neurodegeneration with brain iron accumulation, Huntington disease-like syndrome due to C9ORF72 expansions, variably protease-sensitive prionopathy, corticobasal syndrome, sensorineural hearing loss-early graying-essential tremor syndrome, progressive supranuclear palsy, Sandifer syndrome, psychogenic movement disorders, epilepsy with myoclonic absences, infantile hypotonia-oculomotor anomalies-hyperkinetic movements-developmental delay syndrome, childhood-onset benign chorea with striatal involvement, childhood-onset motor and cognitive regression syndrome with extrapyramidal movement disorder, PRRT2-associated paroxysmal movement disorder, SLC6A3-related dopamine transporter deficiency syndrome, dyskinesia with orofacial involvement, autosomal dominant, complex movement disorder with or without neurodevelopmental features

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

45 retrieved; paginated sample, class counts are floors:

11 uncertain significance, 9 conflicting classifications of pathogenicity, 6 likely pathogenic, 6 pathogenic, 3 pathogenic/likely pathogenic, 3 not provided, 3 benign, 2 benign/likely benign, 2 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
161418	NM_000100.4(CSTB):c.136C>T (p.Gln46Ter)	CSTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
55956	NG_011545.1(CSTB):g.4900_4935CCCCGCCCCGCG[30_125]	CSTB	Pathogenic	no assertion criteria provided
55960	NM_000100.4(CSTB):c.218_219del (p.Leu73fs)	CSTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
575156	NM_000100.4(CSTB):c.64C>T (p.Gln22Ter)	CSTB	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
8395	NM_000100.4(CSTB):c.67-1G>C	CSTB	Pathogenic	criteria provided, multiple submitters, no conflicts
8396	NM_000100.4(CSTB):c.202C>T (p.Arg68Ter)	CSTB	Pathogenic	criteria provided, multiple submitters, no conflicts
8397	NM_000100.4(CSTB):c.10G>C (p.Gly4Arg)	CSTB	Pathogenic	no assertion criteria provided
8398	NM_000100.3(CSTB):c.-210CCCCGCCCCGCG[2_3]	CSTB	Pathogenic	no assertion criteria provided
8400	NM_000100.4(CSTB):c.212A>C (p.Gln71Pro)	CSTB	Pathogenic	no assertion criteria provided
3376548	NM_000100.4(CSTB):c.76C>T (p.Gln26Ter)	CSTB	Likely pathogenic	criteria provided, single submitter
431700	NM_000100.4(CSTB):c.10G>T (p.Gly4Trp)	CSTB	Likely pathogenic	criteria provided, single submitter
55957	NM_000100.4(CSTB):c.125C>A (p.Ser42Ter)	CSTB	Likely pathogenic	no assertion criteria provided
55958	NM_000100.4(CSTB):c.168G>A (p.Lys56=)	CSTB	Likely pathogenic	no assertion criteria provided
55959	NM_000100.4(CSTB):c.169-2A>G	CSTB	Likely pathogenic	no assertion criteria provided
55961	NM_000100.4(CSTB):c.66G>A (p.Gln22=)	CSTB	Likely pathogenic	no assertion criteria provided
195015	NM_000100.4(CSTB):c.121G>A (p.Val41Met)	CSTB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
205323	NM_000100.4(CSTB):c.193G>A (p.Val65Ile)	CSTB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340115	NM_000100.3(CSTB):c.*355C>G	CSTB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340121	NM_000100.4(CSTB):c.169-14C>T	CSTB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340122	NM_000100.3(CSTB):c.-42C>T	CSTB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
382295	NM_000100.4(CSTB):c.45G>A (p.Glu15=)	CSTB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
502097	NM_000100.4(CSTB):c.251_254del (p.Asn84fs)	CSTB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
510088	NM_000100.4(CSTB):c.-12G>A	CSTB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
895890	NM_000100.4(CSTB):c.9C>T (p.Cys3=)	CSTB	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
340114	NM_000100.3(CSTB):c.*435G>A	CSTB	Uncertain significance	criteria provided, single submitter
340117	NM_000100.3(CSTB):c.*301G>A	CSTB	Uncertain significance	criteria provided, single submitter
340118	NM_000100.4(CSTB):c.*227A>G	CSTB	Uncertain significance	criteria provided, single submitter
340123	NM_000100.3(CSTB):c.-43C>G	CSTB	Uncertain significance	criteria provided, single submitter
566232	NM_000100.4(CSTB):c.158A>G (p.Tyr53Cys)	CSTB	Uncertain significance	criteria provided, multiple submitters, no conflicts
896110	NM_000100.3(CSTB):c.*334G>A	CSTB	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 13 · Orphanet: 6 · 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
CSTB	Definitive	Autosomal recessive	Unverricht-Lundborg syndrome	4
PRICKLE1	Supportive	Autosomal recessive	Unverricht-Lundborg syndrome	4
SCARB2	Supportive	Autosomal recessive	Unverricht-Lundborg syndrome	5

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CSTB	Orphanet:248	Autosomal recessive hypohidrotic ectodermal dysplasia
CSTB	Orphanet:308	Progressive myoclonic epilepsy type 1
SCARB2	Orphanet:163696	Action myoclonus-renal failure syndrome
SCARB2	Orphanet:308	Progressive myoclonic epilepsy type 1
SCARB2	Orphanet:77259	Gaucher disease type 1
PRICKLE1	Orphanet:308	Progressive myoclonic epilepsy type 1

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
CSTB	HGNC:2482	ENSG00000160213	P04080	Cystatin-B	gencc,clinvar
SCARB2	HGNC:1665	ENSG00000138760	Q14108	Lysosome membrane protein 2	gencc
PRICKLE1	HGNC:17019	ENSG00000139174	Q96MT3	Prickle-like protein 1	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CSTB	Cystatin-B	This is an intracellular thiol proteinase inhibitor.
SCARB2	Lysosome membrane protein 2	Acts as a lysosomal receptor for glucosylceramidase (GBA1) targeting.
PRICKLE1	Prickle-like protein 1	Involved in the planar cell polarity pathway that controls convergent extension during gastrulation and neural tube closure.

Protein-family classification

Druggable: 0 · Difficult: 1 · Unknown: 2 · 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	2.8×	0.587
Other/Unknown	2	1.2×	0.587

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CSTB	Other/Unknown	no		Cystatin_dom, Prot_inh_stefin, Prot_inh_cystat_CS
SCARB2	Other/Unknown	no		CD36_fam, LimpII
PRICKLE1	Transcription factor	no		Znf_LIM, PET_domain, PET_prickle

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
lower esophagus mucosa	1
pharyngeal mucosa	1
tongue squamous epithelium	1
germinal epithelium of ovary	1
inferior vagus X ganglion	1
subthalamic nucleus	1
buccal mucosa cell	1
lateral nuclear group of thalamus	1
tendon of biceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CSTB	300	ubiquitous	marker	lower esophagus mucosa, tongue squamous epithelium, pharyngeal mucosa
SCARB2	298	ubiquitous	marker	inferior vagus X ganglion, subthalamic nucleus, germinal epithelium of ovary
PRICKLE1	243	ubiquitous	marker	buccal mucosa cell, tendon of biceps brachii, lateral nuclear group of thalamus

Protein interactions among cohort

Intra-cohort edges: 1.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCARB2	5,405
CSTB	1,987
PRICKLE1	1,485

Intra-cohort edges

A	B	Sources
CSTB	PRICKLE1	string_interaction

Structural data

PDB: 2 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCARB2	Q14108	10
CSTB	P04080	3

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PRICKLE1	Q96MT3	55.55

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 3 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
Asymmetric localization of PCP proteins	1	68.0×	0.070	PRICKLE1
Cargo recognition for clathrin-mediated endocytosis	1	34.9×	0.070	SCARB2
Clathrin-mediated endocytosis	1	28.4×	0.070	SCARB2
Membrane Trafficking	1	12.4×	0.100	SCARB2
Vesicle-mediated transport	1	11.6×	0.100	SCARB2
Neutrophil degranulation	1	7.7×	0.124	CSTB

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of carbohydrate catabolic process	1	5617.3×	0.004	SCARB2
regulation of glucosylceramide catabolic process	1	5617.3×	0.004	SCARB2
polarized secretion of basement membrane proteins in epithelium	1	2808.7×	0.004	PRICKLE1
regulation of endosome organization	1	2808.7×	0.004	SCARB2
anterior visceral endoderm cell migration	1	2808.7×	0.004	PRICKLE1
negative regulation of cardiac muscle cell myoblast differentiation	1	2808.7×	0.004	PRICKLE1
establishment of bipolar cell polarity involved in cell morphogenesis	1	1872.4×	0.004	PRICKLE1
focal adhesion disassembly	1	1872.4×	0.004	PRICKLE1
aminophospholipid transport	1	1404.3×	0.004	SCARB2
renal tubule development	1	1404.3×	0.004	PRICKLE1
tear secretion	1	1404.3×	0.004	PRICKLE1
maintenance of postsynaptic density structure	1	1404.3×	0.004	PRICKLE1
embryonic nail plate morphogenesis	1	1123.5×	0.004	PRICKLE1
endosome to plasma membrane protein transport	1	1123.5×	0.004	SCARB2
regulation of lysosome organization	1	936.2×	0.004	SCARB2
mesenchyme development	1	802.5×	0.005	PRICKLE1
primitive streak formation	1	468.1×	0.007	PRICKLE1
cornea development in camera-type eye	1	432.1×	0.008	PRICKLE1
eyelid development in camera-type eye	1	351.1×	0.009	PRICKLE1
cytoskeleton-dependent intracellular transport	1	312.1×	0.009	PRICKLE1
extracellular matrix assembly	1	312.1×	0.009	PRICKLE1
regulation of postsynaptic density assembly	1	295.6×	0.009	PRICKLE1
embryonic brain development	1	267.5×	0.010	PRICKLE1
post-anal tail morphogenesis	1	244.2×	0.010	PRICKLE1
negative regulation of proteolysis	1	224.7×	0.010	CSTB
response to electrical stimulus	1	216.1×	0.010	PRICKLE1
protein targeting to lysosome	1	208.1×	0.010	SCARB2
cardiac muscle cell development	1	208.1×	0.010	PRICKLE1
coronary vasculature development	1	208.1×	0.010	PRICKLE1
tissue homeostasis	1	187.2×	0.010	PRICKLE1

Therapeutics

Drugs indicated for this disease

0 approved, 2 in late-stage (phase 3) trials. Disease-direct ChEMBL indications, not inferred from the associated-gene cohort below.

Drug	Development status
Brivaracetam	Phase 3 (in late-stage trials)
Human Immunoglobulin G	Phase 3 (in late-stage trials)

Earlier-phase candidates (phase 2, investigational — efficacy not yet established): Ropinirole.

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CSTB	0	0
SCARB2	0	0
PRICKLE1	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
CSTB	1	Binding:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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	3	CSTB, SCARB2, PRICKLE1

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
CSTB	1	—
SCARB2	0	—
PRICKLE1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	3
PHASE2	1
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00357669	PHASE3	COMPLETED	Brivaracetam as add-on Treatment of Unverricht-Lundborg Disease in Adolescents and Adults
NCT00368251	PHASE3	COMPLETED	Brivaracetam as add-on Treatment of Unverricht-Lundborg Disease (ULD) in Adolescents and Adults
NCT03351569	PHASE3	UNKNOWN	Intravenous Immunoglobulin for Unverricht-Lundborg Disease.
NCT00639119	PHASE2	UNKNOWN	Effect of Ropinirole Hydrochloride in Progressive Myoclonic Epilepsy of Unverricht-Lundborg Type
NCT06593951	Not specified	RECRUITING	Registry and Natural History Study for Progressive Myoclonus Epilepsy Type 1 (EPM1)

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
ROPINIROLE	4	3
BRIVARACETAM	4	1