Dystonia 9

Summary

Dystonia 9 (MONDO:0010983) is a disease caused by SLC2A1 (GenCC Strong), with 3 cohort genes and 1 clinical trial.

At a glance

• Prevalence: <1 / 1 000 000 (Worldwide) [Orphanet-validated]
• Causal gene: SLC2A1 (GenCC Strong)
• Cohort genes: 3
• ClinVar variants: 244
• Phenotypes (HPO): 13
• Clinical trials: 1

Clinical features

Epidemiology

Prevalence records

2 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Cases/families		20	Worldwide	Validated
Point prevalence	<1 / 1 000 000		Worldwide	Validated

Signs & symptoms

Clinical features (HPO)

13 HPO clinical features (Orphanet curated; top 13 by frequency):

HPO ID	Term	Frequency
HP:0007166	Paroxysmal dyskinesia	Very frequent (80-99%)
HP:0000651	Diplopia	Frequent (30-79%)
HP:0001249	Intellectual disability	Frequent (30-79%)
HP:0001258	Spastic paraplegia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001266	Choreoathetosis	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0001347	Hyperreflexia	Frequent (30-79%)
HP:0002131	Episodic ataxia	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0003401	Paresthesia	Frequent (30-79%)
HP:0007256	Abnormal pyramidal sign	Frequent (30-79%)
HP:0002069	Bilateral tonic-clonic seizure	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	dystonia 9
Mondo ID	MONDO:0010983
MeSH	C563401
OMIM	601042
Orphanet	53583
DOID	DOID:0090044
SNOMED CT	715564000
UMLS	C1832855
MedGen	371427
GARD	0016656
Is cancer (heuristic)	no

Also known as: dystonia 9 · dystonia type 9 · DYT9 · episodic choreoathetosis/spasticity

Data availability: 244 ClinVar variants · 3 GenCC gene-disease records.

Disease family

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 › dystonia 9

Related subtypes (2): 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

244 retrieved; paginated sample, class counts are floors:

95 uncertain significance, 34 likely benign, 30 conflicting classifications of pathogenicity, 30 benign, 26 benign/likely benign, 20 pathogenic, 6 pathogenic/likely pathogenic, 3 likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1189059	NM_006516.4(SLC2A1):c.399C>A (p.Cys133Ter)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1335936	NM_006516.4(SLC2A1):c.739G>T (p.Glu247Ter)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
159921	NM_006516.4(SLC2A1):c.100A>G (p.Asn34Asp)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
16113	NM_006516.4(SLC2A1):c.940G>A (p.Gly314Ser)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
16118	NM_006516.4(SLC2A1):c.376C>T (p.Arg126Cys)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686198	NM_006516.4(SLC2A1):c.1287_1288del (p.Cys429fs)	SLC2A1	Pathogenic	criteria provided, single submitter
1686199	NM_006516.4(SLC2A1):c.1206_1215dup (p.Val406fs)	SLC2A1	Pathogenic	criteria provided, single submitter
1686200	NM_006516.4(SLC2A1):c.1135_1147del (p.Phe379fs)	SLC2A1	Pathogenic	criteria provided, single submitter
1686201	NM_006516.4(SLC2A1):c.635del (p.Arg212fs)	SLC2A1	Pathogenic	criteria provided, single submitter
1686202	NM_006516.4(SLC2A1):c.524G>T (p.Gly175Val)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1686203	NM_006516.4(SLC2A1):c.115-2A>C	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
1686204	NM_006516.4(SLC2A1):c.37dup (p.Met13fs)	SLC2A1	Pathogenic	criteria provided, single submitter
1686205	NM_006516.4(SLC2A1):c.29del (p.Gly10fs)	SLC2A1	Pathogenic	criteria provided, single submitter
198842	NM_006516.4(SLC2A1):c.997C>T (p.Arg333Trp)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207193	NM_006516.4(SLC2A1):c.667C>T (p.Arg223Trp)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
207196	NM_006516.4(SLC2A1):c.988C>T (p.Arg330Ter)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
207202	NM_006516.4(SLC2A1):c.972G>A (p.Ser324=)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
207212	NM_006516.4(SLC2A1):c.1198C>T (p.Arg400Cys)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
207225	NM_006516.4(SLC2A1):c.19-2A>G	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
2430183	NM_006516.4(SLC2A1):c.1141del (p.Val381fs)	SLC2A1	Pathogenic	criteria provided, single submitter
37300	NM_006516.4(SLC2A1):c.634C>T (p.Arg212Cys)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
619980	NM_006516.4(SLC2A1):c.161dup (p.Ser55fs)	SLC2A1	Pathogenic	criteria provided, single submitter
662199	NM_006516.4(SLC2A1):c.101A>G (p.Asn34Ser)	SLC2A1	Pathogenic	criteria provided, multiple submitters, no conflicts
96708	NM_006516.4(SLC2A1):c.1372C>T (p.Arg458Trp)	SLC2A1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
973266	NM_006516.4(SLC2A1):c.1028dup (p.Met344fs)	SLC2A1	Pathogenic	criteria provided, single submitter
1686206	NM_006516.4(SLC2A1):c.1A>G (p.Met1Val)	SLC2A1-DT	Pathogenic	criteria provided, multiple submitters, no conflicts
3906995	NM_004208.4(AIFM1):c.169T>C (p.Ser57Pro)	AIFM1	Likely pathogenic	criteria provided, single submitter
2585125	NM_006516.4(SLC2A1):c.194G>A (p.Trp65Ter)	SLC2A1	Likely pathogenic	criteria provided, single submitter
4057316	NM_006516.4(SLC2A1):c.428A>G (p.Tyr143Cys)	SLC2A1	Likely pathogenic	criteria provided, single submitter
1203673	NM_006516.4(SLC2A1):c.1297G>A (p.Val433Ile)	SLC2A1	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 14 · Orphanet: 11 · 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
SLC2A1	Strong	Autosomal dominant	dystonia 9	14

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
AIFM1	Orphanet:101078	X-linked Charcot-Marie-Tooth disease type 4
AIFM1	Orphanet:139583	X-linked hereditary sensory and autonomic neuropathy with deafness
AIFM1	Orphanet:238329	Severe X-linked mitochondrial encephalomyopathy
AIFM1	Orphanet:83629	Leukoencephalopathy-spondyloepimetaphyseal dysplasia syndrome

Cohort genes → proteins

3 cohort genes, 2 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SLC2A1	HGNC:11005	ENSG00000117394	P11166	Solute carrier family 2, facilitated glucose transporter member 1	gencc,clinvar
SLC2A1-DT	HGNC:44187	ENSG00000227533		SLC2A1 divergent transcript	clinvar
AIFM1	HGNC:8768	ENSG00000156709	O95831	Apoptosis-inducing factor 1, mitochondrial	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.
AIFM1	Apoptosis-inducing factor 1, mitochondrial	Functions both as NADH oxidoreductase and as regulator of apoptosis.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 1 · Druggable fraction: 0.67

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	25.9×	0.114
Enzyme (other)	1	4.0×	0.345
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SLC2A1	Transporter	yes		Glu_transpt_1, Sugar/inositol_transpt, MFS_sugar_transport-like
SLC2A1-DT	Other/Unknown	no
AIFM1	Enzyme (other)	yes	7.1.1.2	FAD/NAD-linked_Rdtase_dimer_sf, FAD/NAD-binding_dom, AIF_C

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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
skin of abdomen	1
sural nerve	1
tibial nerve	1
lateral globus pallidus	1
sperm	1
vena cava	1
adult mammalian kidney	1
apex of heart	1
heart left ventricle	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
SLC2A1-DT	168	ubiquitous	yes	sperm, vena cava, lateral globus pallidus
AIFM1	273	ubiquitous	marker	apex of heart, adult mammalian kidney, heart left ventricle

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SLC2A1	5,711
AIFM1	4,780
SLC2A1-DT	0

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
AIFM1	O95831	26
SLC2A1	P11166	5

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 5. Enrichment computed across 3 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
Defective SLC2A1 causes GLUT1 deficiency syndrome 1 (GLUT1DS1)	1	11420.0×	4e-04	SLC2A1
Lactose synthesis	1	3806.7×	7e-04	SLC2A1
Vitamin C (ascorbate) metabolism	1	1427.5×	0.001	SLC2A1
Cellular hexose transport	1	543.8×	0.002	SLC2A1
Regulation of insulin secretion	1	219.6×	0.005	SLC2A1

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
protein import into mitochondrial intermembrane space	1	2808.7×	0.003	AIFM1
protein import into the intermembrane space via the disulfide relay system	1	2808.7×	0.003	AIFM1
response to Thyroglobulin triiodothyronine	1	2808.7×	0.003	SLC2A1
long-chain fatty acid import across plasma membrane	1	2106.5×	0.003	SLC2A1
GDP-L-fucose salvage	1	2106.5×	0.003	SLC2A1
mitochondrial respiratory chain complex assembly	1	1404.3×	0.003	AIFM1
positive regulation of necroptotic process	1	1404.3×	0.003	AIFM1
D-glucose import across plasma membrane	1	1404.3×	0.003	SLC2A1
cellular response to aldosterone	1	1203.7×	0.003	AIFM1
response to L-glutamate	1	842.6×	0.004	AIFM1
L-ascorbic acid metabolic process	1	766.0×	0.004	SLC2A1
dehydroascorbic acid transport	1	601.9×	0.005	SLC2A1
cellular hyperosmotic response	1	601.9×	0.005	SLC2A1
cellular response to nitric oxide	1	468.1×	0.005	AIFM1
D-glucose transmembrane transport	1	468.1×	0.005	SLC2A1
obsolete D-glucose import	1	421.3×	0.005	SLC2A1
intrinsic apoptotic signaling pathway in response to endoplasmic reticulum stress	1	240.7×	0.009	AIFM1
cellular response to estradiol stimulus	1	205.5×	0.010	AIFM1
photoreceptor cell maintenance	1	179.3×	0.011	SLC2A1
cellular response to glucose starvation	1	168.5×	0.011	SLC2A1
positive regulation of neuron apoptotic process	1	135.9×	0.012	AIFM1
response to ischemia	1	125.8×	0.012	AIFM1
cellular response to hydrogen peroxide	1	117.0×	0.012	AIFM1
response to insulin	1	115.4×	0.012	SLC2A1
cellular response to mechanical stimulus	1	108.0×	0.012	SLC2A1
female pregnancy	1	105.3×	0.012	SLC2A1
response to toxic substance	1	105.3×	0.012	AIFM1
cerebral cortex development	1	102.8×	0.012	SLC2A1
transport across blood-brain barrier	1	89.6×	0.014	SLC2A1
cellular response to hypoxia	1	60.6×	0.020	AIFM1

Therapeutics

Drug target analysis

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

Druggability breadth: 2 of 3 evidence-associated genes (67%) 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SLC2A1	7	4
SLC2A1-DT	0	0
AIFM1	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
EMETINE	4	SLC2A1
GOSSYPOL	3	SLC2A1
CYCLOHEXIMIDE	2	SLC2A1
GENISTEIN	2	SLC2A1
COLFORSIN	2	SLC2A1
KAEMPFEROL	1	SLC2A1
PD-0166285	1	SLC2A1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
SLC2A1	158	Binding:130, ADMET:24, Functional:4
AIFM1	2	Binding:2

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
AIFM1	7.1.1.2	NADH:ubiquinone reductase (H+-translocating)

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SLC2A1	158

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; 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)
EMETINE	4	SLC2A1
GOSSYPOL	3	SLC2A1
CYCLOHEXIMIDE	2	SLC2A1
GENISTEIN	2	SLC2A1
COLFORSIN	2	SLC2A1
KAEMPFEROL	1	SLC2A1
PD-0166285	1	SLC2A1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SLC2A1
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	AIFM1
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	SLC2A1-DT

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)
SLC2A1-DT	0	—
AIFM1	2	—

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
NCT03428009	Not specified	RECRUITING	Dystonia Genotype-Phenotype Correlation