Paroxysmal dystonia

Summary

Paroxysmal dystonia (MONDO:0016058) is a disease with 5 cohort genes.

At a glance

• Cohort genes: 5
• ClinVar variants: 7

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	paroxysmal dystonia
Mondo ID	MONDO:0016058
Orphanet	200037
ICD-11	2047715743
SNOMED CT	230310003
UMLS	C0393588
MedGen	97951
GARD	0020340
Is cancer (heuristic)	no

Data availability: 7 ClinVar variants.

Disease family

An umbrella term covering 3 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

Related subtypes (9): myoclonus-dystonia syndrome, dystonia 12, X-linked dystonia-parkinsonism, dystonia 16, parkinsonism-dystonia, infantile, infantile epileptic-dyskinetic encephalopathy, ataxia - telangiectasia variant, combined cervical dystonia, dystonia-aphonia syndrome

Subtypes (3): dystonia 9, paroxysmal dyskinesia, benign paroxysmal torticollis of infancy

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

7 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic, 2 pathogenic, 1 conflicting classifications of pathogenicity, 1 uncertain significance, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
523448	NM_002016.2(FLG):c.544A>T (p.Lys182Ter)	CCDST	Pathogenic	criteria provided, single submitter
1892	NM_015488.5(PNKD):c.26C>T (p.Ala9Val)	LOC129935594	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
689477	NM_002599.5(PDE2A):c.1180C>T (p.Gln394Ter)	PDE2A	Pathogenic	criteria provided, single submitter
374181	NM_006516.4(SLC2A1):c.400G>A (p.Gly134Ser)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
553552	NM_000287.4(PEX6):c.2356C>T (p.Arg786Trp)	PEX6	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
869197	NM_000287.4(PEX6):c.371T>C (p.Leu124Pro)	PEX6	Uncertain significance	criteria provided, single submitter
978813	NM_000834.5(GRIN2B):c.3638A>T (p.Asn1213Ile)	GRIN2B	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 14 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SLC2A1	Orphanet:168577	Hereditary cryohydrocytosis with reduced stomatin
SLC2A1	Orphanet:1942	Epilepsy with myoclonic-atonic seizures
SLC2A1	Orphanet:2131	Alternating hemiplegia of childhood
SLC2A1	Orphanet:53583	Paroxysmal dystonic choreathetosis with episodic ataxia and spasticity
SLC2A1	Orphanet:71277	Classic glucose transporter type 1 deficiency syndrome
SLC2A1	Orphanet:86911	Epilepsy with myoclonic absences
SLC2A1	Orphanet:98811	Paroxysmal exertion-induced dyskinesia
GRIN2B	Orphanet:589547	GRIN2B-related developmental delay, intellectual disability and autism spectrum disorder
GRIN2B	Orphanet:697160	Infantile epileptic spasms syndrome
PEX6	Orphanet:3220	Deafness-enamel hypoplasia-nail defects syndrome
PEX6	Orphanet:44	Neonatal adrenoleukodystrophy
PEX6	Orphanet:772	Infantile Refsum disease
PEX6	Orphanet:912	Zellweger syndrome
PEX6	Orphanet:95433	Autosomal recessive spinocerebellar ataxia-blindness-deafness syndrome

Cohort genes → proteins

5 cohort genes, 4 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC2A1	HGNC:11005	ENSG00000117394	P11166	Solute carrier family 2, facilitated glucose transporter member 1	clinvar
GRIN2B	HGNC:4586	ENSG00000273079	Q13224	Glutamate receptor ionotropic, NMDA 2B	clinvar
CCDST	HGNC:55988	ENSG00000236427		cervical cancer associated DHX9 suppressive transcript	clinvar
PDE2A	HGNC:8777	ENSG00000186642	O00408	cGMP-dependent 3’,5’-cyclic phosphodiesterase	clinvar
PEX6	HGNC:8859	ENSG00000124587	Q13608	Peroxisomal ATPase PEX6	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SLC2A1	Solute carrier family 2, facilitated glucose transporter member 1	Facilitative glucose transporter, which is responsible for constitutive or basal glucose uptake.
GRIN2B	Glutamate receptor ionotropic, NMDA 2B	Component of N-methyl-D-aspartate (NMDA) receptors (NMDARs) that function as heterotetrameric, ligand-gated cation channels with high calcium permeability and voltage-dependent block by Mg(2+).
PDE2A	cGMP-dependent 3’,5’-cyclic phosphodiesterase	cGMP-activated cyclic nucleotide phosphodiesterase with a dual-specificity for the second messengers cAMP and cGMP, which are key regulators of many important physiological processes.
PEX6	Peroxisomal ATPase PEX6	Component of the PEX1-PEX6 AAA ATPase complex, a protein dislocase complex that mediates the ATP-dependent extraction of the PEX5 receptor from peroxisomal membranes, an essential step for PEX5 recycling.

Protein-family classification

Druggable: 2 · Difficult: 1 · Unknown: 2 · Druggable fraction: 0.4

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
Transporter	1	15.6×	0.251
Enzyme (other)	1	2.4×	0.634
Transcription factor	1	1.6×	0.634
Other/Unknown	2	0.7×	0.877

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC2A1	Transporter	yes		Glu_transpt_1, Sugar/inositol_transpt, MFS_sugar_transport-like
GRIN2B	Other/Unknown	no		Iontro_rcpt_C, Iono_Glu_rcpt_met, ANF_lig-bd_rcpt
CCDST	Other/Unknown	no
PDE2A	Transcription factor	no	3.1.4.17	PDEase_catalytic_dom, GAF, HD/PDEase_dom
PEX6	Enzyme (other)	yes	3.6.4.7	AAA+_ATPase, ATPase_AAA_core, ATPase_AAA_CS

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)	5
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	1
sural nerve	1
tibial nerve	1
Brodmann (1909) area 23	1
buccal mucosa cell	1
cortical plate	1
lower esophagus mucosa	1
male germ line stem cell (sensu Vertebrata) in testis	1
quadriceps femoris	1
prefrontal cortex	1
right frontal lobe	1
spleen	1
body of pancreas	1
mucosa of transverse colon	1
right uterine tube	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SLC2A1	250	ubiquitous	marker	tibial nerve, sural nerve, skin of abdomen
GRIN2B	138	broad	marker	buccal mucosa cell, cortical plate, Brodmann (1909) area 23
CCDST	111	broad	yes	male germ line stem cell (sensu Vertebrata) in testis, lower esophagus mucosa, quadriceps femoris
PDE2A	224	broad	marker	spleen, right frontal lobe, prefrontal cortex
PEX6	227	ubiquitous	marker	right uterine tube, body of pancreas, mucosa of transverse colon

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC2A1	5,711
GRIN2B	3,611
PEX6	2,620
PDE2A	1,283
CCDST	0

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 1

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
PDE2A	O00408	44
GRIN2B	Q13224	36
SLC2A1	P11166	5

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
PEX6	Q13608	69.87

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 19. Enrichment computed across 5 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
Defective SLC2A1 causes GLUT1 deficiency syndrome 1 (GLUT1DS1)	1	2855.0×	0.007	SLC2A1
Lactose synthesis	1	951.7×	0.010	SLC2A1
Activated NTRK2 signals through FYN	1	475.8×	0.013	GRIN2B
Vitamin C (ascorbate) metabolism	1	356.9×	0.013	SLC2A1
cGMP effects	1	178.4×	0.013	PDE2A
MECP2 regulates neuronal receptors and channels	1	150.3×	0.013	GRIN2B
Ras activation upon Ca2+ influx through NMDA receptor	1	142.8×	0.013	GRIN2B
Cellular hexose transport	1	135.9×	0.013	SLC2A1
Unblocking of NMDA receptors, glutamate binding and activation	1	135.9×	0.013	GRIN2B
Synaptic adhesion-like molecules	1	135.9×	0.013	GRIN2B
Negative regulation of NMDA receptor-mediated neuronal transmission	1	135.9×	0.013	GRIN2B
Long-term potentiation	1	119.0×	0.013	GRIN2B
EPHB-mediated forward signaling	1	66.4×	0.021	GRIN2B
Assembly and cell surface presentation of NMDA receptors	1	63.4×	0.021	GRIN2B
Regulation of insulin secretion	1	54.9×	0.023	SLC2A1
Neurexins and neuroligins	1	49.2×	0.024	GRIN2B
Peroxisomal protein import	1	43.3×	0.026	PEX6
G alpha (s) signalling events	1	18.3×	0.057	PDE2A
RAF/MAP kinase cascade	1	15.3×	0.064	GRIN2B

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
response to Thyroglobulin triiodothyronine	1	1404.3×	0.008	SLC2A1
cellular response to 2,3,7,8-tetrachlorodibenzodioxine	1	1404.3×	0.008	PDE2A
long-chain fatty acid import across plasma membrane	1	1053.2×	0.008	SLC2A1
protein import into peroxisome matrix, translocation	1	1053.2×	0.008	PEX6
GDP-L-fucose salvage	1	1053.2×	0.008	SLC2A1
cellular response to macrophage colony-stimulating factor stimulus	1	842.6×	0.008	PDE2A
protein unfolding	1	842.6×	0.008	PEX6
cGMP catabolic process	1	842.6×	0.008	PDE2A
negative regulation of receptor guanylyl cyclase signaling pathway	1	702.2×	0.008	PDE2A
D-glucose import across plasma membrane	1	702.2×	0.008	SLC2A1
negative regulation of dendritic spine maintenance	1	702.2×	0.008	GRIN2B
cellular response to mechanical stimulus	2	108.0×	0.008	SLC2A1, PDE2A
protein import into peroxisome matrix, receptor recycling	1	601.9×	0.008	PEX6
cellular response to cGMP	1	526.6×	0.008	PDE2A
regulation of monoatomic cation transmembrane transport	1	526.6×	0.008	GRIN2B
protein targeting to peroxisome	1	421.3×	0.008	PEX6
negative regulation of adenylate cyclase-activating G protein-coupled receptor signaling pathway	1	421.3×	0.008	PDE2A
heart valve development	1	383.0×	0.008	PDE2A
L-ascorbic acid metabolic process	1	383.0×	0.008	SLC2A1
calcium ion transmembrane import into cytosol	1	383.0×	0.008	GRIN2B
protein import into peroxisome matrix	1	351.1×	0.008	PEX6
ionotropic glutamate receptor signaling pathway	1	324.1×	0.008	GRIN2B
positive regulation of vascular permeability	1	324.1×	0.008	PDE2A
cellular response to granulocyte macrophage colony-stimulating factor stimulus	1	324.1×	0.008	PDE2A
excitatory chemical synaptic transmission	1	324.1×	0.008	GRIN2B
dehydroascorbic acid transport	1	300.9×	0.008	SLC2A1
cellular hyperosmotic response	1	300.9×	0.008	SLC2A1
negative regulation of vascular permeability	1	280.9×	0.009	PDE2A
protein heterotetramerization	1	263.3×	0.009	GRIN2B
glutamate receptor signaling pathway	1	234.1×	0.009	GRIN2B

Therapeutics

Drug target analysis

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

Druggability breadth: 3 of 5 evidence-associated genes (60%) 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
SLC2A1	EMETINE
GRIN2B	HALOPERIDOL
PDE2A	VARDENAFIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
GRIN2B	35	4
PDE2A	12	4
SLC2A1	7	4
CCDST	0	0
PEX6	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EMETINE	4	SLC2A1
HALOPERIDOL	4	GRIN2B
DEXTROMETHORPHAN	4	GRIN2B
KETAMINE	4	GRIN2B
CYCLOSERINE	4	GRIN2B
MEMANTINE	4	GRIN2B
TACRINE	4	GRIN2B
LEVORPHANOL	4	GRIN2B
AMANTADINE	4	GRIN2B
CHLORPROMAZINE	4	GRIN2B
PROCYCLIDINE	4	GRIN2B
ORPHENADRINE	4	GRIN2B
VARDENAFIL	4	PDE2A
CLOFARABINE	4	PDE2A
SILDENAFIL	4	PDE2A
ANAGRELIDE	4	PDE2A
DIPYRIDAMOLE	4	PDE2A
GOSSYPOL	3	SLC2A1
DALZANEMDOR	3	GRIN2B
LATREPIRDINE	3	GRIN2B
ESMETHADONE	3	GRIN2B
GLUTAMIC ACID	3	GRIN2B
PAPAVERINE	3	PDE2A
CYCLOHEXIMIDE	2	SLC2A1
GENISTEIN	2	SLC2A1
COLFORSIN	2	SLC2A1
TRAXOPRODIL	2	GRIN2B
ELIPRODIL	2	GRIN2B
IFENPRODIL	2	GRIN2B
EVT-101 FREE BASE	2	GRIN2B

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 2.

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

Symbol	Assays	Type breakdown
GRIN2B	471	Binding:429, Functional:36, ADMET:5, Toxicity:1
PDE2A	346	Binding:331, ADMET:8, Functional:7
SLC2A1	158	Binding:130, ADMET:24, Functional:4

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
PDE2A	3.1.4.17	3’,5’-cyclic-nucleotide phosphodiesterase
PEX6	3.6.4.7	peroxisome-assembly ATPase

Cohort genes with high screening signal

≥100 ChEMBL assays — a studied-ness signal; see Therapeutics for approved-drug status.

Symbol	ChEMBL assays
SLC2A1	158
GRIN2B	471
PDE2A	346

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

30 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)
EMETINE	4	SLC2A1
HALOPERIDOL	4	GRIN2B
DEXTROMETHORPHAN	4	GRIN2B
KETAMINE	4	GRIN2B
CYCLOSERINE	4	GRIN2B
MEMANTINE	4	GRIN2B
TACRINE	4	GRIN2B
LEVORPHANOL	4	GRIN2B
AMANTADINE	4	GRIN2B
CHLORPROMAZINE	4	GRIN2B
PROCYCLIDINE	4	GRIN2B
ORPHENADRINE	4	GRIN2B
VARDENAFIL	4	PDE2A
CLOFARABINE	4	PDE2A
SILDENAFIL	4	PDE2A
ANAGRELIDE	4	PDE2A
DIPYRIDAMOLE	4	PDE2A
GOSSYPOL	3	SLC2A1
DALZANEMDOR	3	GRIN2B
LATREPIRDINE	3	GRIN2B
ESMETHADONE	3	GRIN2B
GLUTAMIC ACID	3	GRIN2B
PAPAVERINE	3	PDE2A
CYCLOHEXIMIDE	2	SLC2A1
GENISTEIN	2	SLC2A1
COLFORSIN	2	SLC2A1
TRAXOPRODIL	2	GRIN2B
ELIPRODIL	2	GRIN2B
IFENPRODIL	2	GRIN2B
EVT-101 FREE BASE	2	GRIN2B

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	3	SLC2A1, GRIN2B, PDE2A
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	0
D	Druggable family + AlphaFold only, no drug	1	PEX6
E	Difficult family or no structure, no drug	1	CCDST

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)
CCDST	0	—
PEX6	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.