Early-onset generalized limb-onset dystonia

Summary

Early-onset generalized limb-onset dystonia (MONDO:0007492) is a disease caused by TOR1A (GenCC Definitive), with 2 cohort genes and 2 clinical trials.

At a glance

• Prevalence: 1-9 / 1 000 000 (Europe) [Orphanet-validated]
• Causal gene: TOR1A (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 61
• Phenotypes (HPO): 5
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

5 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000	0.4	Europe	Validated
Annual incidence	1-5 / 10 000	20	Specific population	Validated
Annual incidence	1-9 / 1 000 000	0.2	United States	Validated
Point prevalence	1-9 / 100 000	3.4	United States	Validated
Prevalence at birth	1-9 / 100 000	8.3	France	Validated

Signs & symptoms

Clinical features (HPO)

5 HPO clinical features (Orphanet curated; top 5 by frequency):

HPO ID	Term	Frequency
HP:0001276	Hypertonia	Very frequent (80-99%)
HP:0001288	Gait disturbance	Very frequent (80-99%)
HP:0003011	Abnormality of the musculature	Very frequent (80-99%)
HP:0100022	Abnormality of movement	Very frequent (80-99%)
HP:0001608	Abnormality of the voice	Frequent (30-79%)

Identifiers

Disease identifiers

Field	Value
Canonical name	early-onset generalized limb-onset dystonia
Mondo ID	MONDO:0007492
MeSH	C538005
OMIM	128100
Orphanet	256
DOID	DOID:0060730
NCIT	C116718
UMLS	C1851945
MedGen	338823
GARD	0002027
Is cancer (heuristic)	no

Also known as: dystonia 1 · dystonia 1, torsion, Autosomal dominant · dystonia 1, torsion, autosomal dominant · dystonia musculorum deformans · dystonia musculorum deformans 1 · dystonia-1, torsion · DYT-TOR1A · DYT-TOR1A dystonia · DYT1 · Dyt1 · early onset primary dystonia · early onset torsion dystonia · early-onset generalised torsion dystonia · early-onset generalized limb-onset dystonia · early-onset generalized torsion dystonia · Early-onset Primary dystonia · early-onset primary dystonia · Early-onset torsion dystonia · early-onset torsion dystonia · EOTD (+7 more)

Data availability: 61 ClinVar variants · 7 GenCC gene-disease records · 41 cell lines.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: human disease › disease by body system or component › nervous system disorder › movement disorder › extrapyramidal and movement disease › dystonic disorder › inherited dystonia › isolated dystonia › generalized dystonia › early-onset generalized dystonia › early-onset generalized limb-onset dystonia

Subtypes (1): torsion dystonia with onset in 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

61 retrieved; paginated sample, class counts are floors:

26 uncertain significance, 13 benign, 5 conflicting classifications of pathogenicity, 5 likely benign, 4 benign/likely benign, 3 pathogenic, 3 not provided, 2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1172768	NM_000113.3(TOR1A):c.214C>T (p.Gln72Ter)	TOR1A	Pathogenic	criteria provided, single submitter
1686266	NM_000113.3(TOR1A):c.958A>G (p.Lys320Glu)	TOR1A	Pathogenic	criteria provided, single submitter
1686267	NM_000113.3(TOR1A):c.461G>A (p.Trp154Ter)	TOR1A	Pathogenic	criteria provided, single submitter
5180	NM_000113.3(TOR1A):c.904GAG[1] (p.Glu303del)	TOR1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
559927	NM_000113.3(TOR1A):c.862C>T (p.Arg288Ter)	TOR1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1308622	NM_000113.3(TOR1A):c.466C>T (p.Arg156Ter)	TOR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
162491	NM_000113.3(TOR1A):c.863G>A (p.Arg288Gln)	TOR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
18438	NM_000113.3(TOR1A):c.613T>A (p.Phe205Ile)	TOR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
268213	NM_000113.3(TOR1A):c.361G>A (p.Glu121Lys)	TOR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
695773	NM_000113.3(TOR1A):c.823A>G (p.Lys275Glu)	TOR1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1683721	NM_000113.3(TOR1A):c.20T>G (p.Val7Gly)	LOC130002772	Uncertain significance	criteria provided, multiple submitters, no conflicts
365235	NM_000113.3(TOR1A):c.-4G>C	LOC130002772	Uncertain significance	criteria provided, multiple submitters, no conflicts
365236	NM_000113.3(TOR1A):c.-31C>A	LOC130002772	Uncertain significance	criteria provided, single submitter
1028074	NM_000113.3(TOR1A):c.620+3A>T	TOR1A	Uncertain significance	criteria provided, single submitter
268214	NM_000113.3(TOR1A):c.385G>A (p.Val129Ile)	TOR1A	Uncertain significance	criteria provided, multiple submitters, no conflicts
365210	NM_000113.3(TOR1A):c.*1010A>G	TOR1A	Uncertain significance	criteria provided, single submitter
365213	NM_000113.3(TOR1A):c.*934A>G	TOR1A	Uncertain significance	criteria provided, single submitter
365217	NM_000113.3(TOR1A):c.*812C>G	TOR1A	Uncertain significance	criteria provided, single submitter
365218	NM_000113.3(TOR1A):c.*785G>A	TOR1A	Uncertain significance	criteria provided, single submitter
365219	NM_000113.3(TOR1A):c.*623C>T	TOR1A	Uncertain significance	criteria provided, single submitter
365226	NM_000113.3(TOR1A):c.*345C>T	TOR1A	Uncertain significance	criteria provided, single submitter
365227	NM_000113.3(TOR1A):c.*216C>T	TOR1A	Uncertain significance	criteria provided, single submitter
365230	NM_000113.3(TOR1A):c.*165G>A	TOR1A	Uncertain significance	criteria provided, single submitter
365231	NM_000113.3(TOR1A):c.*149G>A	TOR1A	Uncertain significance	criteria provided, single submitter
365233	NM_000113.3(TOR1A):c.300G>A (p.Leu100=)	TOR1A	Uncertain significance	criteria provided, single submitter
5181	NM_000113.3(TOR1A):c.966_983del (p.Phe323_Tyr328del)	TOR1A	Uncertain significance	no assertion criteria provided
816839	NM_000113.3(TOR1A):c.506T>C (p.Phe169Ser)	TOR1A	Uncertain significance	criteria provided, single submitter
912676	NM_000113.3(TOR1A):c.*201G>A	TOR1A	Uncertain significance	criteria provided, single submitter
913780	NM_000113.3(TOR1A):c.*165G>T	TOR1A	Uncertain significance	criteria provided, single submitter
913781	NM_000113.3(TOR1A):c.*108G>C	TOR1A	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 17 · Orphanet: 3 · 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
TOR1A	Definitive	Autosomal dominant	early-onset generalized limb-onset dystonia	10
EIF2AK2	Supportive	Autosomal dominant	early-onset generalized limb-onset dystonia	7

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TOR1A	Orphanet:256	Early-onset generalized limb-onset dystonia
TOR1A	Orphanet:36899	Myoclonus-dystonia syndrome
EIF2AK2	Orphanet:256	Early-onset generalized limb-onset dystonia

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
TOR1A	HGNC:3098	ENSG00000136827	O14656	Torsin-1A	gencc,clinvar
EIF2AK2	HGNC:9437	ENSG00000055332	P19525	Interferon-induced, double-stranded RNA-activated protein kinase	gencc

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TOR1A	Torsin-1A	Protein with chaperone functions important for the control of protein folding, processing, stability and localization as well as for the reduction of misfolded protein aggregates.
EIF2AK2	Interferon-induced, double-stranded RNA-activated protein kinase	IFN-induced dsRNA-dependent serine/threonine-protein kinase that phosphorylates the alpha subunit of eukaryotic translation initiation factor 2 (EIF2S1/eIF-2-alpha) and plays a key role in the innate immune response to viral infection.

Protein-family classification

Druggable: 1 · Difficult: 0 · 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
Kinase	1	13.9×	0.142
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TOR1A	Other/Unknown	no		Torsin, Torsin_1/2, P-loop_NTPase
EIF2AK2	Kinase	yes		Prot_kinase_dom, Ser/Thr_kinase_AS, Kinase-like_dom_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
monocyte	1
secondary oocyte	1
stromal cell of endometrium	1
buccal mucosa cell	1
choroid plexus epithelium	1
endometrium epithelium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TOR1A	274	ubiquitous	marker	stromal cell of endometrium, secondary oocyte, monocyte
EIF2AK2	296	ubiquitous	marker	endometrium epithelium, buccal mucosa cell, choroid plexus epithelium

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
EIF2AK2	4,520
TOR1A	1,304

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
EIF2AK2	P19525	12
TOR1A	O14656	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 7. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Inhibition of PKR	1	5710.0×	0.001	EIF2AK2
SUMOylation of immune response proteins	1	475.8×	0.007	EIF2AK2
Evasion by RSV of host interferon responses	1	163.1×	0.014	EIF2AK2
Interferon alpha/beta signaling	1	76.1×	0.016	EIF2AK2
ISG15 antiviral mechanism	1	75.1×	0.016	EIF2AK2
PKR-mediated signaling	1	70.5×	0.016	EIF2AK2
Cargo recognition for clathrin-mediated endocytosis	1	52.4×	0.019	TOR1A

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 NLRP3 inflammasome complex assembly	1	4213.0×	0.005	EIF2AK2
regulation of hematopoietic stem cell proliferation	1	2808.7×	0.005	EIF2AK2
synaptic vesicle membrane organization	1	1685.2×	0.005	TOR1A
regulation of hematopoietic progenitor cell differentiation	1	1685.2×	0.005	EIF2AK2
positive regulation of synaptic vesicle endocytosis	1	1404.3×	0.005	TOR1A
regulation of dopamine uptake involved in synaptic transmission	1	1203.7×	0.005	TOR1A
nuclear membrane organization	1	1203.7×	0.005	TOR1A
response to interferon-alpha	1	842.6×	0.005	EIF2AK2
regulation of protein localization to cell surface	1	842.6×	0.005	TOR1A
negative regulation of osteoblast proliferation	1	766.0×	0.005	EIF2AK2
regulation of hematopoietic stem cell differentiation	1	766.0×	0.005	EIF2AK2
protein deneddylation	1	648.1×	0.005	TOR1A
wound healing, spreading of cells	1	561.7×	0.006	TOR1A
nuclear envelope organization	1	495.6×	0.006	TOR1A
intermediate filament cytoskeleton organization	1	468.1×	0.006	TOR1A
synaptic vesicle transport	1	421.3×	0.006	TOR1A
positive regulation of stress-activated MAPK cascade	1	401.2×	0.006	EIF2AK2
regulation of translational initiation	1	234.1×	0.010	EIF2AK2
positive regulation of chemokine production	1	187.2×	0.011	EIF2AK2
negative regulation of viral genome replication	1	187.2×	0.011	EIF2AK2
protein localization to nucleus	1	175.5×	0.011	TOR1A
cellular response to amino acid starvation	1	159.0×	0.012	EIF2AK2
endoplasmic reticulum unfolded protein response	1	147.8×	0.012	EIF2AK2
positive regulation of cytokine production	1	135.9×	0.013	EIF2AK2
positive regulation of non-canonical NF-kappaB signal transduction	1	127.7×	0.013	EIF2AK2
antiviral innate immune response	1	113.9×	0.014	EIF2AK2
obsolete positive regulation of NF-kappaB transcription factor activity	1	102.8×	0.015	EIF2AK2
negative regulation of translation	1	98.0×	0.015	EIF2AK2
ERAD pathway	1	90.6×	0.016	TOR1A
protein autophosphorylation	1	72.6×	0.018	EIF2AK2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 2 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
EIF2AK2	FEDRATINIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
EIF2AK2	19	4
TOR1A	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
FEDRATINIB	4	EIF2AK2
AXITINIB	4	EIF2AK2
PAZOPANIB	4	EIF2AK2
SUNITINIB	4	EIF2AK2
ERLOTINIB	4	EIF2AK2
CRIZOTINIB	4	EIF2AK2
MIDOSTAURIN	4	EIF2AK2
ALVOCIDIB	3	EIF2AK2
DOVITINIB	3	EIF2AK2
LESTAURTINIB	3	EIF2AK2
SU-014813	2	EIF2AK2
R-406	2	EIF2AK2
BI-2536	2	EIF2AK2
RAF-265	2	EIF2AK2
PELITINIB	2	EIF2AK2
KW-2449	1	EIF2AK2
SU-9516	1	EIF2AK2
GSK-690693	1	EIF2AK2
AST-487	1	EIF2AK2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
EIF2AK2	213	Binding:213

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
EIF2AK2	213

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

19 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)
FEDRATINIB	4	EIF2AK2
AXITINIB	4	EIF2AK2
PAZOPANIB	4	EIF2AK2
SUNITINIB	4	EIF2AK2
ERLOTINIB	4	EIF2AK2
CRIZOTINIB	4	EIF2AK2
MIDOSTAURIN	4	EIF2AK2
ALVOCIDIB	3	EIF2AK2
DOVITINIB	3	EIF2AK2
LESTAURTINIB	3	EIF2AK2
SU-014813	2	EIF2AK2
R-406	2	EIF2AK2
BI-2536	2	EIF2AK2
RAF-265	2	EIF2AK2
PELITINIB	2	EIF2AK2
KW-2449	1	EIF2AK2
SU-9516	1	EIF2AK2
GSK-690693	1	EIF2AK2
AST-487	1	EIF2AK2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	EIF2AK2
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	1	TOR1A

Undrugged target profiles

1 cohort genes are undrugged. Ranked by ‘starting-point quality’ (assay depth + drugged-partner adjacency).

Symbol	ChEMBL assays	Drugged partners (top 3)
TOR1A	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
Not specified	2

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07168850	Not specified	RECRUITING	Focused Ultrasound Unilateral Pallidotomy for Medication-Refractory Limb Dystonia
NCT01435681	Not specified	COMPLETED	Can Short Latency Afferent Inhibition Give us Clues to Better DYT 1 Dystonia Treatments?