Generalized epilepsy-paroxysmal dyskinesia syndrome

Summary

Generalized epilepsy-paroxysmal dyskinesia syndrome (MONDO:0012276) is a disease caused by KCNMA1 (GenCC Definitive), with 4 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: KCNMA1 (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 1,165
• Phenotypes (HPO): 11

Clinical features

Signs & symptoms

Clinical features (HPO)

11 HPO clinical features (Orphanet curated; top 11 by frequency):

HPO ID	Term	Frequency
HP:0002197	Generalized-onset seizure	Frequent (30-79%)
HP:0007166	Paroxysmal dyskinesia	Frequent (30-79%)
HP:0010849	EEG with spike-wave complexes (>3.5 Hz)	Frequent (30-79%)
HP:0000565	Esotropia	Occasional (5-29%)
HP:0000639	Nystagmus	Occasional (5-29%)
HP:0001263	Global developmental delay	Occasional (5-29%)
HP:0001290	Generalized hypotonia	Occasional (5-29%)
HP:0002069	Bilateral tonic-clonic seizure	Occasional (5-29%)
HP:0002072	Chorea	Occasional (5-29%)
HP:0002121	Generalized non-motor (absence) seizure	Occasional (5-29%)
HP:0006889	Intellectual disability, borderline	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	generalized epilepsy-paroxysmal dyskinesia syndrome
Mondo ID	MONDO:0012276
MeSH	C563719
OMIM	609446
Orphanet	79137
DOID	DOID:0070442
UMLS	C5574945
MedGen	1801137
GARD	0016704
Is cancer (heuristic)	no

Also known as: generalised epilepsy and paroxysmal dyskinesia · generalized epilepsy and paroxysmal dyskinesia · GEPD · paroxysmal nonkinesigenic dyskinesia, 3, with or without generalised epilepsy · PNKD3

Data availability: 1,165 ClinVar variants · 6 GenCC gene-disease records.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › central nervous system disorder › brain disorder › epilepsy › focal epilepsy › familial partial epilepsy › generalized epilepsy-paroxysmal dyskinesia syndrome

Related subtypes (6): familial sleep-related hypermotor epilepsy, temporal lobe epilepsy, self-limited epilepsy with centrotemporal spikes, autosomal dominant epilepsy with auditory features, familial focal epilepsy with variable foci, mesial temporal lobe epilepsy with hippocampal sclerosis

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:

306 likely benign, 236 uncertain significance, 20 conflicting classifications of pathogenicity, 13 benign, 9 benign/likely benign, 8 likely pathogenic, 7 pathogenic, 1 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1072449	NM_001161352.2(KCNMA1):c.302dup (p.Leu102fs)	KCNMA1	Pathogenic	criteria provided, single submitter
1414943	NM_001161352.2(KCNMA1):c.1284del (p.Leu429fs)	KCNMA1	Pathogenic	criteria provided, single submitter
1447009	NM_001161352.2(KCNMA1):c.70_73del (p.Leu23_Arg24insTer)	KCNMA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1458025	NC_000010.10:g.(?78998319)(79163801_?)del	KCNMA1	Pathogenic	criteria provided, single submitter
1685896	NM_001161352.2(KCNMA1):c.1437del (p.Lys480fs)	KCNMA1	Pathogenic	criteria provided, single submitter
265313	NM_001161352.2(KCNMA1):c.3158A>G (p.Asn1053Ser)	KCNMA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2704729	NM_001161352.2(KCNMA1):c.1869del (p.Phe623fs)	KCNMA1	Pathogenic	criteria provided, single submitter
1416721	NM_001161352.2(KCNMA1):c.2521del (p.His841fs)	KCNMA1-AS1	Pathogenic	criteria provided, single submitter
1098715	NM_000217.3(KCNA1):c.1186G>C (p.Gly396Arg)	KCNA1	Likely pathogenic	criteria provided, single submitter
1004014	NM_001161352.2(KCNMA1):c.1807A>G (p.Thr603Ala)	KCNMA1	Likely pathogenic	criteria provided, single submitter
1479179	NM_001161352.2(KCNMA1):c.574C>A (p.Leu192Ile)	KCNMA1	Likely pathogenic	criteria provided, single submitter
1506973	NM_001161352.2(KCNMA1):c.2092+1G>A	KCNMA1	Likely pathogenic	criteria provided, single submitter
1519204	NC_000010.10:g.(?78998319)(79163801_?)dup	KCNMA1	Likely pathogenic	criteria provided, single submitter
216948	NM_001161352.2(KCNMA1):c.1054A>G (p.Thr352Ala)	KCNMA1	Likely pathogenic	criteria provided, single submitter
2424381	NC_000010.10:g.(?78943159)(78944694_?)dup	KCNMA1	Likely pathogenic	criteria provided, single submitter
2702333	NM_001161352.2(KCNMA1):c.3016+2T>C	KCNMA1-AS1	Likely pathogenic	criteria provided, single submitter
1011015	NM_001161352.2(KCNMA1):c.3547G>A (p.Gly1183Ser)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1047433	NM_001161352.2(KCNMA1):c.514G>A (p.Ala172Thr)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1096688	NM_001161352.2(KCNMA1):c.70A>C (p.Arg24=)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1142924	NM_001161352.2(KCNMA1):c.3471C>T (p.Ile1157=)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1208963	NM_001161352.2(KCNMA1):c.1989C>T (p.Ile663=)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
129320	NM_001161352.2(KCNMA1):c.1680C>A (p.Ala560=)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1301635	NM_001161352.2(KCNMA1):c.2267-4486C>T	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1342465	NM_001161352.2(KCNMA1):c.1332C>T (p.His444=)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1345098	NM_001161352.2(KCNMA1):c.117CTC[11] (p.Ser57_Ser60dup)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1402247	NM_001161352.2(KCNMA1):c.179C>T (p.Ser60Leu)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193225	NM_001161352.2(KCNMA1):c.36CGG[8] (p.Gly20dup)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193227	NM_001161352.2(KCNMA1):c.192C>G (p.Pro64=)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
193230	NM_001161352.2(KCNMA1):c.162_173del (p.Ser57_Ser60del)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
194371	NM_001161352.2(KCNMA1):c.1641C>T (p.Asp547=)	KCNMA1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 11 · Orphanet: 7 · 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
KCNMA1	Definitive	Autosomal dominant	generalized epilepsy-paroxysmal dyskinesia syndrome	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNMA1	Orphanet:664438	Gingival fibromatosis-aortic root dilatation-facial dysmorphism-intellectual disability syndrome
KCNMA1	Orphanet:79137	Generalized epilepsy-paroxysmal dyskinesia syndrome
KCNA1	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
KCNA1	Orphanet:199326	Isolated autosomal dominant hypomagnesemia, Glaudemans type
KCNA1	Orphanet:37612	Episodic ataxia type 1
KCNA1	Orphanet:972	Hereditary continuous muscle fiber activity
KCNA1	Orphanet:98809	Paroxysmal kinesigenic dyskinesia

Cohort genes → proteins

4 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
KCNMA1	HGNC:6284	ENSG00000156113	Q12791	Calcium-activated potassium channel subunit alpha-1	gencc,clinvar
DLG5	HGNC:2904	ENSG00000151208	Q8TDM6	Disks large homolog 5	clinvar
KCNMA1-AS1	HGNC:51213	ENSG00000236467		KCNMA1 antisense RNA 1	clinvar
KCNA1	HGNC:6218	ENSG00000111262	Q09470	Potassium voltage-gated channel subfamily A member 1	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNMA1	Calcium-activated potassium channel subunit alpha-1	Potassium channel activated by both membrane depolarization or increase in cytosolic Ca(2+) that mediates export of K(+).
DLG5	Disks large homolog 5	Acts as a regulator of the Hippo signaling pathway.
KCNA1	Potassium voltage-gated channel subfamily A member 1	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the kidney.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 1 · 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
Ion channel	2	55.8×	0.001
Scaffold/PPI	1	4.3×	0.318
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
KCNMA1	Ion channel	yes		RCK_N, K_chnl_BK_asu, Ion_trans_dom
DLG5	Scaffold/PPI	no		CARD, SH3_domain, PDZ
KCNMA1-AS1	Other/Unknown	no
KCNA1	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv

Expression context

Cohort genes with no expression data: 0.

4 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)	4
unknown	0

Top tissues across cohort

Tissue	Cohort genes
parotid gland	1
saphenous vein	1
tibia	1
left adrenal gland cortex	1
right adrenal gland cortex	1
ventricular zone	1
calcaneal tendon	1
male germ line stem cell (sensu Vertebrata) in testis	1
sural nerve	1
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNMA1	275	ubiquitous	marker	parotid gland, saphenous vein, tibia
DLG5	134	ubiquitous	marker	ventricular zone, left adrenal gland cortex, right adrenal gland cortex
KCNMA1-AS1	154		marker	calcaneal tendon, male germ line stem cell (sensu Vertebrata) in testis, sural nerve
KCNA1	151	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNA1	3,157
KCNMA1	2,606
DLG5	2,544
KCNMA1-AS1	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNMA1	Q12791	36
DLG5	Q8TDM6	1

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNA1	Q09470	78.74

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 18. Enrichment computed across 4 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
Potassium Channels	2	89.6×	0.003	KCNMA1, KCNA1
Acetylcholine inhibits contraction of outer hair cells	1	761.3×	0.009	KCNMA1
Neuronal System	2	29.5×	0.009	KCNMA1, KCNA1
Ca2+ activated K+ channels	1	380.7×	0.012	KCNMA1
Nitric oxide stimulates guanylate cyclase	1	271.9×	0.013	KCNMA1
cGMP effects	1	237.9×	0.013	KCNMA1
Sensory processing of sound	1	102.9×	0.016	KCNMA1
RHOV GTPase cycle	1	95.2×	0.016	DLG5
Platelet homeostasis	1	92.8×	0.016	KCNMA1
RHOU GTPase cycle	1	92.8×	0.016	DLG5
RND1 GTPase cycle	1	88.5×	0.016	DLG5
RND3 GTPase cycle	1	86.5×	0.016	DLG5
RND2 GTPase cycle	1	86.5×	0.016	DLG5
Voltage gated Potassium channels	1	81.0×	0.016	KCNA1
Sensory processing of sound by outer hair cells of the cochlea	1	68.0×	0.018	KCNMA1
Sensory processing of sound by inner hair cells of the cochlea	1	54.4×	0.021	KCNMA1
Sensory Perception	1	31.7×	0.033	KCNMA1
Hemostasis	1	12.0×	0.081	KCNMA1

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 membrane potential	2	153.9×	0.003	KCNMA1, KCNA1
potassium ion transmembrane transport	2	90.6×	0.004	KCNMA1, KCNA1
zonula adherens assembly	1	2808.7×	0.004	DLG5
response to carbon monoxide	1	1872.4×	0.004	KCNMA1
micturition	1	1872.4×	0.004	KCNMA1
cell communication by electrical coupling	1	1404.3×	0.004	KCNA1
detection of mechanical stimulus involved in sensory perception of touch	1	1404.3×	0.004	KCNA1
smooth muscle contraction involved in micturition	1	1404.3×	0.004	KCNMA1
negative regulation of cell volume	1	1123.5×	0.004	KCNMA1
protein localization to adherens junction	1	1123.5×	0.004	DLG5
polarized epithelial cell differentiation	1	936.2×	0.004	DLG5
neuronal signal transduction	1	802.5×	0.004	KCNA1
maintenance of cell polarity	1	802.5×	0.004	DLG5
cellular response to magnesium ion	1	802.5×	0.004	KCNA1
postsynapse organization	1	802.5×	0.004	DLG5
magnesium ion homeostasis	1	624.1×	0.005	KCNA1
regulation of muscle contraction	1	561.7×	0.005	KCNA1
metanephric collecting duct development	1	561.7×	0.005	DLG5
membrane repolarization during action potential	1	561.7×	0.005	KCNA1
response to osmotic stress	1	510.7×	0.005	KCNMA1
neuroepithelial cell differentiation	1	510.7×	0.005	DLG5
startle response	1	374.5×	0.006	KCNA1
detection of mechanical stimulus involved in sensory perception of pain	1	374.5×	0.006	KCNA1
positive regulation of hippo signaling	1	351.1×	0.006	DLG5
intracellular potassium ion homeostasis	1	330.4×	0.006	KCNMA1
apical protein localization	1	330.4×	0.006	DLG5
glial cell differentiation	1	295.6×	0.007	DLG5
epithelial tube branching involved in lung morphogenesis	1	280.9×	0.007	DLG5
positive regulation of dendritic spine development	1	255.3×	0.007	DLG5
negative regulation of hippo signaling	1	234.1×	0.008	DLG5

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 4 evidence-associated genes (50%) have a ChEMBL target (buckets above are over the deeply-mined display cohort).

Genes with an approved drug

The molecule shown is one approved compound that hits the gene — not necessarily a drug of choice or one indicated for this disease.

Symbol	Example approved molecule
KCNMA1	CANNABIDIOL
KCNA1	NIFEDIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNA1	5	4
KCNMA1	2	4
DLG5	0	0
KCNMA1-AS1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CANNABIDIOL	4	KCNMA1
NIFEDIPINE	4	KCNA1
DALFAMPRIDINE	4	KCNA1
CAPSAICIN	4	KCNA1
FLINDOKALNER	3	KCNMA1
CORTISONE	3	KCNA1
TETRYLAMMONIUM	2	KCNA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNMA1	94	Binding:91, Functional:2, Toxicity:1
KCNA1	59	Binding:52, Functional:6, Toxicity: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

7 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.

Compound	Max phase	Cohort target (bioactivity)
CANNABIDIOL	4	KCNMA1
NIFEDIPINE	4	KCNA1
DALFAMPRIDINE	4	KCNA1
CAPSAICIN	4	KCNA1
FLINDOKALNER	3	KCNMA1
CORTISONE	3	KCNA1
TETRYLAMMONIUM	2	KCNA1

Druggability pyramid

Cohort genes binned by druggability tier (high → low):

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	KCNMA1, KCNA1
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	DLG5, KCNMA1-AS1

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)
DLG5	0	—
KCNMA1-AS1	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.