Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer's cramp syndrome

Summary

Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome (MONDO:0011970) is a disease with 2 cohort genes.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 31
• Phenotypes (HPO): 8

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

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

Signs & symptoms

Clinical features (HPO)

8 HPO clinical features (Orphanet curated; top 8 by frequency):

HPO ID	Term	Frequency
HP:0000666	Horizontal nystagmus	Frequent (30-79%)
HP:0002268	Paroxysmal dystonia	Frequent (30-79%)
HP:0002356	Writer’s cramp	Frequent (30-79%)
HP:0007104	Prolonged somatosensory evoked potentials	Frequent (30-79%)
HP:0007332	Focal hemifacial clonic seizure	Frequent (30-79%)
HP:0011295	EEG with parietal sharp waves	Frequent (30-79%)
HP:0012012	EEG with parietal focal spike waves	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome
Mondo ID	MONDO:0011970
MeSH	C535499
OMIM	608105
Orphanet	163727
DOID	DOID:0111645
ICD-11	1311096281
UMLS	C1842531
MedGen	334104
GARD	0017003
Is cancer (heuristic)	no

Also known as: epilepsy, rolandic, with paroxysmal exercise-induce dystonia and writer’s cramp · epilepsy, ROLANDIC, with paroxysmal exercise-induced dystonia and writer’S cramp · EPRPDC

Data availability: 31 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › epilepsy syndrome › childhood-onset epilepsy syndrome › rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome

Related subtypes (15): self-limited childhood occipital epilepsy, Landau-Kleffner syndrome, perioral myoclonia with absences, cryptogenic late-onset epileptic spasms, rolandic epilepsy-speech dyspraxia syndrome, early-onset epileptic encephalopathy and intellectual disability due to GRIN2A mutation, familial partial epilepsy, acute encephalopathy with biphasic seizures and late reduced diffusion, new-onset refractory status epilepticus, atypical childhood epilepsy with centrotemporal spikes, Sunflower syndrome, childhood-onset genetic generalized epilepsy syndrome, childhood-onset idiopathic generalized epilepsy syndrome, childhood-onset epilepsy syndrome with developmental and/or epileptic encephalopathy, childhood-onset self-limited focal epilepsy syndrome

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

31 retrieved; paginated sample, class counts are floors:

15 uncertain significance, 4 pathogenic, 4 benign/likely benign, 3 conflicting classifications of pathogenicity, 3 likely pathogenic, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1071941	NM_001199107.2(TBC1D24):c.642_793del (p.Trp215fs)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts
419296	NM_001199107.2(TBC1D24):c.1499C>T (p.Ala500Val)	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
421795	NM_001199107.2(TBC1D24):c.1360_1363dup (p.Pro455fs)	TBC1D24	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
474302	NM_001199107.2(TBC1D24):c.116C>T (p.Ala39Val)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts
523796	NM_001199107.2(TBC1D24):c.619C>T (p.Gln207Ter)	TBC1D24	Pathogenic	criteria provided, multiple submitters, no conflicts
652618	NM_001199107.2(TBC1D24):c.1501G>A (p.Gly501Arg)	TBC1D24	Pathogenic	no assertion criteria provided
3338428	GRCh37/hg19 16p13.3(chr16:2229815-2582030)x4	E4F1	Likely pathogenic	no assertion criteria provided
3256791	NM_001199107.2(TBC1D24):c.857T>C (p.Leu286Pro)	TBC1D24	Likely pathogenic	no assertion criteria provided
652619	NM_001199107.2(TBC1D24):c.1079G>A (p.Arg360His)	TBC1D24	Likely pathogenic	criteria provided, single submitter
130541	NM_001199107.2(TBC1D24):c.1015A>G (p.Asn339Asp)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
227980	NM_001199107.2(TBC1D24):c.1570C>T (p.Arg524Trp)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
418692	NM_001199107.2(TBC1D24):c.229ATCGTGGGCAAG[1] (p.77IVGK[1])	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1213711	NM_001199107.2(TBC1D24):c.1142+272T>C	TBC1D24	Uncertain significance	criteria provided, single submitter
1696584	NM_001199107.2(TBC1D24):c.-116+125A>C	TBC1D24	Uncertain significance	criteria provided, single submitter
207501	NM_001199107.2(TBC1D24):c.605C>T (p.Ser202Leu)	TBC1D24	Uncertain significance	criteria provided, multiple submitters, no conflicts
207519	NM_001199107.2(TBC1D24):c.878G>A (p.Arg293His)	TBC1D24	Uncertain significance	criteria provided, multiple submitters, no conflicts
229287	NM_001199107.2(TBC1D24):c.439G>A (p.Asp147Asn)	TBC1D24	Uncertain significance	criteria provided, multiple submitters, no conflicts
2584794	NM_001199107.2(TBC1D24):c.571T>C (p.Cys191Arg)	TBC1D24	Uncertain significance	criteria provided, single submitter
3382995	NM_001199107.2(TBC1D24):c.469C>G (p.Arg157Gly)	TBC1D24	Uncertain significance	criteria provided, single submitter
392542	NM_001199107.2(TBC1D24):c.1633A>G (p.Ile545Val)	TBC1D24	Uncertain significance	criteria provided, multiple submitters, no conflicts
425089	NM_001199107.2(TBC1D24):c.1367C>A (p.Pro456Gln)	TBC1D24	Uncertain significance	criteria provided, multiple submitters, no conflicts
474312	NM_001199107.2(TBC1D24):c.808C>T (p.Arg270Cys)	TBC1D24	Uncertain significance	criteria provided, multiple submitters, no conflicts
626176	NM_001199107.2(TBC1D24):c.734T>C (p.Leu245Pro)	TBC1D24	Uncertain significance	criteria provided, multiple submitters, no conflicts
655487	NM_001199107.2(TBC1D24):c.217G>A (p.Val73Met)	TBC1D24	Uncertain significance	criteria provided, multiple submitters, no conflicts
662069	NM_001199107.2(TBC1D24):c.1426G>A (p.Ala476Thr)	TBC1D24	Uncertain significance	criteria provided, multiple submitters, no conflicts
936514	NM_001199107.2(TBC1D24):c.601G>A (p.Val201Met)	TBC1D24	Uncertain significance	criteria provided, multiple submitters, no conflicts
969480	NM_001199107.2(TBC1D24):c.1393G>A (p.Ala465Thr)	TBC1D24	Uncertain significance	criteria provided, multiple submitters, no conflicts
130534	NM_001199107.2(TBC1D24):c.1143-6C>T	TBC1D24	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
130535	NM_001199107.2(TBC1D24):c.1326C>T (p.Tyr442=)	TBC1D24	Benign/Likely benign	criteria provided, multiple submitters, no conflicts
130538	NM_001199107.2(TBC1D24):c.1509C>T (p.Ser503=)	TBC1D24	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 8 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBC1D24	Orphanet:163727	Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome
TBC1D24	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
TBC1D24	Orphanet:352582	Familial infantile myoclonic epilepsy
TBC1D24	Orphanet:352587	Focal epilepsy-intellectual disability-cerebro-cerebellar malformation
TBC1D24	Orphanet:352596	Progressive myoclonic epilepsy with dystonia
TBC1D24	Orphanet:79500	DOORS syndrome
TBC1D24	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TBC1D24	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB

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
TBC1D24	HGNC:29203	ENSG00000162065	Q9ULP9	TBC1 domain family member 24	clinvar
E4F1	HGNC:3121	ENSG00000167967	Q66K89	Transcription factor E4F1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBC1D24	TBC1 domain family member 24	May act as a GTPase-activating protein for Rab family protein(s).
E4F1	Transcription factor E4F1	May function as a transcriptional repressor.

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)
TBC1D24	Other/Unknown	no		Rab-GAP-TBC_dom, TLDc_dom, Rab-GAP_TBC_sf
E4F1	Transcription factor	no		Znf_C2H2_type, Znf_C2H2_sf

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
Brodmann (1909) area 23	1
middle temporal gyrus	1
parotid gland	1
lower esophagus mucosa	1
right hemisphere of cerebellum	1
sural nerve	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBC1D24	227	ubiquitous	marker	parotid gland, Brodmann (1909) area 23, middle temporal gyrus
E4F1	138	ubiquitous	marker	right hemisphere of cerebellum, lower esophagus mucosa, sural nerve

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
E4F1	1,965
TBC1D24	1,016

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
TBC1D24	Q9ULP9	84.46
E4F1	Q66K89	53.68

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 4. Enrichment computed across 2 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
Rab regulation of trafficking	1	368.4×	0.008	TBC1D24
TBC/RABGAPs	1	259.6×	0.008	TBC1D24
Membrane Trafficking	1	37.1×	0.029	TBC1D24
Vesicle-mediated transport	1	34.8×	0.029	TBC1D24

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
regulation of mitotic cell cycle, embryonic	1	8426.0×	0.002	E4F1
negative regulation of cellular response to oxidative stress	1	2106.5×	0.004	TBC1D24
regulation of cell cycle process	1	495.6×	0.008	E4F1
positive regulation of neuron migration	1	495.6×	0.008	TBC1D24
positive regulation of dendrite morphogenesis	1	443.5×	0.008	TBC1D24
positive regulation of excitatory postsynaptic potential	1	263.3×	0.010	TBC1D24
axon development	1	227.7×	0.010	TBC1D24
synaptic vesicle endocytosis	1	216.1×	0.010	TBC1D24
dendrite development	1	195.9×	0.010	TBC1D24
DNA replication	1	82.6×	0.021	E4F1
cellular response to oxidative stress	1	77.3×	0.021	TBC1D24
neuron projection development	1	61.1×	0.024	TBC1D24
regulation of cell cycle	1	37.3×	0.037	E4F1
cell division	1	23.1×	0.055	E4F1
protein ubiquitination	1	20.7×	0.057	E4F1
negative regulation of transcription by RNA polymerase II	1	8.9×	0.123	E4F1
positive regulation of transcription by RNA polymerase II	1	7.4×	0.138	E4F1
regulation of transcription by RNA polymerase II	1	5.8×	0.164	E4F1

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
TBC1D24	0	0
E4F1	0	0

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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	TBC1D24, E4F1

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)
TBC1D24	0	—
E4F1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.