Paroxysmal dyskinesia

Summary

Paroxysmal dyskinesia (MONDO:0015427) is a disease (an umbrella term covering 5 Mondo subtypes) caused by KCNJ10 (GenCC Strong), with 4 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: KCNJ10 (GenCC Strong)
• Umbrella term: 5 Mondo subtypes
• Cohort genes: 4
• ClinVar variants: 3
• Clinical trials: 1

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	paroxysmal dyskinesia
Mondo ID	MONDO:0015427
Orphanet	1431
SNOMED CT	49949003
UMLS	C0752210
MedGen	156242
GARD	0018721
Is cancer (heuristic)	no

Also known as: paroxysmal choreoathetosis · paroxysmal dystonic choreoathetosis

Data availability: 3 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 5 Mondo subtypes.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › movement disorder › extrapyramidal and movement disease › dystonic disorder › inherited dystonia › combined dystonia › paroxysmal dystonia › paroxysmal dyskinesia

Related subtypes (2): dystonia 9, benign paroxysmal torticollis of infancy

Subtypes (5): infantile convulsions and choreoathetosis, childhood onset GLUT1 deficiency syndrome 2, episodic kinesigenic dyskinesia, ECHS1-related paroxysmal dyskinesia, paroxysmal nonkinesigenic dyskinesia

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

3 retrieved; paginated sample, class counts are floors:

1 uncertain significance, 1 pathogenic/likely pathogenic, 1 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1892	NM_015488.5(PNKD):c.26C>T (p.Ala9Val)	LOC129935594	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812926	NC_000010.10:g.129942146_132848717del	MGMT	Likely pathogenic	no assertion criteria provided
1344545	NM_004984.4(KIF5A):c.2767C>T (p.Arg923Trp)	KIF5A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 9 · Orphanet: 9 · 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
KCNJ10	Strong	Autosomal dominant	paroxysmal dyskinesia	8
COMT	Moderate	Autosomal dominant	paroxysmal dyskinesia

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
COMT	Orphanet:567	22q11.2 deletion syndrome
KCNJ10	Orphanet:199343	EAST syndrome
KCNJ10	Orphanet:705	Pendred syndrome
KCNJ10	Orphanet:98809	Paroxysmal kinesigenic dyskinesia
KIF5A	Orphanet:100991	Autosomal dominant spastic paraplegia type 10
KIF5A	Orphanet:324611	Autosomal dominant Charcot-Marie-Tooth disease type 2 due to KIF5A mutation
MGMT	Orphanet:251576	Gliosarcoma
MGMT	Orphanet:251579	Giant cell glioblastoma
MGMT	Orphanet:618	Familial melanoma

Cohort genes → proteins

4 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	4

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
COMT	HGNC:2228	ENSG00000093010	P21964	Catechol O-methyltransferase	gencc
KCNJ10	HGNC:6256	ENSG00000177807	P78508	ATP-sensitive inward rectifier potassium channel 10	gencc
KIF5A	HGNC:6323	ENSG00000155980	Q12840	Kinesin heavy chain isoform 5A	clinvar
MGMT	HGNC:7059	ENSG00000170430	P16455	Methylated-DNA–protein-cysteine methyltransferase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
COMT	Catechol O-methyltransferase	Catalyzes the O-methylation, and thereby the inactivation, of catecholamine neurotransmitters and catechol hormones.
KCNJ10	ATP-sensitive inward rectifier potassium channel 10	May be responsible for potassium buffering action of glial cells in the brain.
KIF5A	Kinesin heavy chain isoform 5A	Microtubule-dependent motor required for slow axonal transport of neurofilament proteins (NFH, NFM and NFL).
MGMT	Methylated-DNA–protein-cysteine methyltransferase	Involved in the cellular defense against the biological effects of O6-methylguanine (O6-MeG) and O4-methylthymine (O4-MeT) in DNA.

Protein-family classification

Druggable: 3 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.75

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	1	27.9×	0.056
Enzyme (other)	2	6.0×	0.056
Other/Unknown	1	0.5×	0.962

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
COMT	Enzyme (other)	yes	2.1.1.6	SAM_O-MeTrfase, Catechol_O-MeTrfase_euk, SAM-dependent_MTases_sf
KCNJ10	Ion channel	yes		K_chnl_inward-rec_Kir1.2, K_chnl_inward-rec_Kir_cyto, Ig_E-set
KIF5A	Other/Unknown	no		Kinesin_motor_dom, Kinesin_motor_CS, P-loop_NTPase
MGMT	Enzyme (other)	yes	2.1.1.63	MethylDNA_cys_MeTrfase_AS, MethylG_MeTrfase_N, MethylDNA_cys_MeTrfase_DNA-bd

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
right adrenal gland	1
right adrenal gland cortex	1
stromal cell of endometrium	1
C1 segment of cervical spinal cord	1
globus pallidus	1
medial globus pallidus	1
cerebellar hemisphere	1
right frontal lobe	1
right hemisphere of cerebellum	1
endometrium epithelium	1
liver	1
right lobe of liver	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
COMT	296	ubiquitous	marker	right adrenal gland cortex, right adrenal gland, stromal cell of endometrium
KCNJ10	185	tissue_specific	marker	C1 segment of cervical spinal cord, medial globus pallidus, globus pallidus
KIF5A	198	broad	marker	right frontal lobe, right hemisphere of cerebellum, cerebellar hemisphere
MGMT	261	ubiquitous	marker	right lobe of liver, liver, endometrium epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
COMT	3,362
KIF5A	3,241
MGMT	2,853
KCNJ10	1,862

Structural data

PDB: 4 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
MGMT	P16455	23
COMT	P21964	12
KCNJ10	P78508	4
KIF5A	Q12840	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 38. Enrichment computed across 4 evidence-associated genes (4 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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
MGMT-mediated DNA damage reversal	1	2855.0×	0.010	MGMT
Enzymatic degradation of Dopamine by monoamine oxidase	1	1427.5×	0.010	COMT
Potassium transport channels	1	951.7×	0.010	KCNJ10
Enzymatic degradation of dopamine by COMT	1	951.7×	0.010	COMT
DNA Damage Reversal	1	407.9×	0.019	MGMT
G protein gated Potassium channels	1	285.5×	0.021	KCNJ10
RHO GTPases activate KTN1	1	259.6×	0.021	KIF5A
Methylation	1	203.9×	0.023	COMT
Inwardly rectifying K+ channels	1	178.4×	0.024	KCNJ10
Activation of GABAB receptors	1	150.3×	0.025	KCNJ10
GABA B receptor activation	1	135.9×	0.025	KCNJ10
Insulin processing	1	114.2×	0.027	KIF5A
Activation of G protein gated Potassium channels	1	98.5×	0.027	KCNJ10
Inhibition of voltage gated Ca2+ channels via Gbeta/gamma subunits	1	98.5×	0.027	KCNJ10
GABA receptor activation	1	79.3×	0.032	KCNJ10
Peptide hormone metabolism	1	68.0×	0.035	KIF5A
Kinesins	1	44.6×	0.050	KIF5A
Potassium Channels	1	33.6×	0.060	KCNJ10
Golgi-to-ER retrograde transport	1	33.2×	0.060	KIF5A
Potential therapeutics for SARS	1	28.6×	0.063	COMT
COPI-dependent Golgi-to-ER retrograde traffic	1	27.7×	0.063	KIF5A
Intra-Golgi and retrograde Golgi-to-ER traffic	1	26.2×	0.063	KIF5A
Neurotransmitter receptors and postsynaptic signal transmission	1	25.0×	0.063	KCNJ10
DNA Repair	1	24.6×	0.063	MGMT
MHC class II antigen presentation	1	22.3×	0.067	KIF5A
Transmission across Chemical Synapses	1	19.0×	0.075	KCNJ10
RHO GTPase Effectors	1	17.0×	0.080	KIF5A
Factors involved in megakaryocyte development and platelet production	1	16.6×	0.080	KIF5A
Neuronal System	1	11.1×	0.114	KCNJ10
Membrane Trafficking	1	9.3×	0.128	KIF5A

GO biological processes by enrichment

Over-representation of cohort genes vs the genome-wide background (hypergeometric test, Benjamini-Hochberg FDR; fold = observed/expected over 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
norepinephrine secretion	1	4213.0×	0.005	COMT
response to dopamine	1	4213.0×	0.005	COMT
catecholamine catabolic process	1	2106.5×	0.005	COMT
glutamate reuptake	1	2106.5×	0.005	KCNJ10
dopamine secretion	1	1404.3×	0.005	COMT
renal filtration	1	1404.3×	0.005	COMT
renin secretion into blood stream	1	1053.2×	0.005	COMT
cellular response to phosphate starvation	1	1053.2×	0.005	COMT
renal sodium excretion	1	1053.2×	0.005	COMT
habituation	1	1053.2×	0.005	COMT
mastication	1	1053.2×	0.005	COMT
methylation	2	85.1×	0.005	COMT, MGMT
renal albumin absorption	1	842.6×	0.006	COMT
retrograde neuronal dense core vesicle transport	1	842.6×	0.006	KIF5A
cerebellar cortex morphogenesis	1	702.2×	0.006	COMT
anterograde dendritic transport of neurotransmitter receptor complex	1	601.9×	0.007	KIF5A
synaptic transmission, dopaminergic	1	526.6×	0.007	COMT
anterograde axonal protein transport	1	526.6×	0.007	KIF5A
response to salt	1	526.6×	0.007	COMT
response to angiotensin	1	468.1×	0.007	COMT
dopamine catabolic process	1	421.3×	0.008	COMT
DNA alkylation repair	1	383.0×	0.008	MGMT
norepinephrine metabolic process	1	383.0×	0.008	COMT
artery development	1	351.1×	0.008	COMT
glomerulus development	1	324.1×	0.008	COMT
regulation of resting membrane potential	1	324.1×	0.008	KCNJ10
cellular response to cocaine	1	324.1×	0.008	COMT
startle response	1	280.9×	0.008	COMT
response to corticosterone	1	280.9×	0.008	COMT
cellular response to potassium ion	1	263.3×	0.008	KCNJ10

Therapeutics

Drug target analysis

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

Druggability breadth: 4 of 4 evidence-associated genes (100%) 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
COMT	OPICAPONE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
COMT	3	4
MGMT	2	3
KCNJ10	0	0
KIF5A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OPICAPONE	4	COMT
TOLCAPONE	4	COMT
ENTACAPONE	4	COMT
6-O-BENZYLGUANINE	3	MGMT
LOMEGUATRIB	2	MGMT

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
MGMT	86	Binding:84, ADMET:2
COMT	55	Binding:47, ADMET:8
KCNJ10	10	Binding:10
KIF5A	8	Binding:8

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
COMT	2.1.1.6	catechol O-methyltransferase
MGMT	2.1.1.63	methylated-DNA-[protein]-cysteine S-methyltransferase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
COMT	1

Chemical tractability of cohort targets

5 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)
OPICAPONE	4	COMT
TOLCAPONE	4	COMT
ENTACAPONE	4	COMT
6-O-BENZYLGUANINE	3	MGMT
LOMEGUATRIB	2	MGMT

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	COMT
B	Phased (≥1) drug, not yet approved	1	MGMT
C	Druggable family + PDB, no drug	1	KCNJ10
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	KIF5A

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)
KCNJ10	10	—
KIF5A	8	—

Clinical trials & evidence

Clinical trials

Clinical trials: 1.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06701851	Not specified	RECRUITING	Neural Correlates of Movement Disorders Associated With PRRT2 Related Paroxysmal Kinesigenic Dyskinesia - an Ancillary Study of AMEDYST Research