Torsion dystonia 2

Summary

Torsion dystonia 2 (MONDO:0009141) is a disease caused by HPCA (GenCC Strong), with 2 cohort genes.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: HPCA (GenCC Strong)
• Cohort genes: 2
• ClinVar variants: 4
• Phenotypes (HPO): 10

Clinical features

Signs & symptoms

Clinical features (HPO)

10 HPO clinical features (Orphanet curated; top 10 by frequency):

HPO ID	Term	Frequency
HP:0001304	Torsion dystonia	Very frequent (80-99%)
HP:0001288	Gait disturbance	Frequent (30-79%)
HP:0000473	Torticollis	Frequent (30-79%)
HP:0000643	Blepharospasm	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001337	Tremor	Frequent (30-79%)
HP:0002451	Limb dystonia	Frequent (30-79%)
HP:0004305	Involuntary movements	Frequent (30-79%)
HP:0011968	Feeding difficulties	Frequent (30-79%)
HP:0007325	Generalized dystonia	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	torsion dystonia 2
Mondo ID	MONDO:0009141
MeSH	C538006
OMIM	224500
Orphanet	99657
DOID	DOID:0090038
NCIT	C123415
UMLS	C1857093
MedGen	346511
GARD	0002028
Is cancer (heuristic)	no

Also known as: autosomal recessive torsion dystonia 2 · dystonia 2, torsion, autosomal recessive · dystonia musculorum deformans type 2 · dystonic disorder caused by mutation in HPCA · DYT2 · HPCA dystonic disorder · torsion dystonia 2, autosomal recessive type · torsion dystonia type 2

Data availability: 4 ClinVar variants · 4 GenCC gene-disease records · 7 cell lines.

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 › isolated dystonia › focal, segmental or multifocal dystonia › torsion dystonia 2

Related subtypes (11): torsion dystonia 4, torsion dystonia 13, torsion dystonia 17, dystonia 23, dystonia 24, dystonia 25, dystonia 27, oromandibular dystonia, blepharospasm-oromandibular dystonia syndrome, infantile-onset generalized dyskinesia with orofacial involvement, adult-onset segmental dystonia

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

4 retrieved; paginated sample, class counts are floors:

2 pathogenic, 1 likely benign, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
190118	NM_002143.3(HPCA):c.225C>A (p.Asn75Lys)	HPCA	Pathogenic	no assertion criteria provided
190119	NM_002143.3(HPCA):c.212C>A (p.Thr71Asn)	HPCA	Pathogenic	no assertion criteria provided
3362294	NM_002143.3(HPCA):c.514G>A (p.Gly172Arg)	HPCA	Uncertain significance	criteria provided, single submitter
190120	NM_002143.3(HPCA):c.568G>A (p.Ala190Thr)	HPCA	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 27 · Orphanet: 8 · 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
CACNA1A	Strong	Autosomal recessive	torsion dystonia 2	23
HPCA	Strong	Autosomal recessive	torsion dystonia 2	4

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
CACNA1A	Orphanet:2131	Alternating hemiplegia of childhood
CACNA1A	Orphanet:2382	Lennox-Gastaut syndrome
CACNA1A	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
CACNA1A	Orphanet:569	Familial or sporadic hemiplegic migraine
CACNA1A	Orphanet:71518	Benign paroxysmal torticollis of infancy
CACNA1A	Orphanet:97	Familial paroxysmal ataxia
CACNA1A	Orphanet:98758	Spinocerebellar ataxia type 6
HPCA	Orphanet:99657	Primary dystonia, DYT2 type

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
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	gencc,clinvar
HPCA	HGNC:5144	ENSG00000121905	P84074	Neuron-specific calcium-binding protein hippocalcin	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
CACNA1A	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	Voltage-sensitive calcium channels (VSCC) mediate the entry of calcium ions into excitable cells and are also involved in a variety of calcium-dependent processes, including muscle contraction, hormone or neurotransmitter release, gene exp…
HPCA	Neuron-specific calcium-binding protein hippocalcin	Calcium-binding protein that may play a role in the regulation of voltage-dependent calcium channels.

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
Ion channel	1	55.8×	0.036
Other/Unknown	1	0.9×	0.805

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
HPCA	Other/Unknown	no		EF_hand_dom, EF-hand-dom_pair, EF_Hand_1_Ca_BS

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
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
caudate nucleus	1
middle frontal gyrus	1
putamen	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
HPCA	189	broad	marker	caudate nucleus, middle frontal gyrus, putamen

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1A	346
HPCA	125

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
CACNA1A	O00555	4
HPCA	P84074	4

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 6. Enrichment computed across 2 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
Presynaptic depolarization and calcium channel opening	1	951.7×	0.006	CACNA1A
Regulation of insulin secretion	1	219.6×	0.011	CACNA1A
Integration of energy metabolism	1	175.7×	0.011	CACNA1A
Transmission across Chemical Synapses	1	76.1×	0.020	CACNA1A
Neuronal System	1	44.3×	0.027	CACNA1A
Metabolism	1	11.6×	0.086	CACNA1A

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 voltage-gated calcium channel activity	1	8426.0×	0.002	HPCA
response to ketamine	1	4213.0×	0.002	HPCA
response to Aroclor 1254	1	2106.5×	0.003	HPCA
cellular response to L-glutamate	1	842.6×	0.006	HPCA
cellular response to electrical stimulus	1	648.1×	0.006	HPCA
response to amyloid-beta	1	495.6×	0.006	CACNA1A
regulation of postsynaptic neurotransmitter receptor internalization	1	312.1×	0.008	HPCA
positive regulation of protein targeting to membrane	1	280.9×	0.008	HPCA
calcium ion import across plasma membrane	1	271.8×	0.008	CACNA1A
cellular response to amyloid-beta	1	195.9×	0.009	CACNA1A
inner ear development	1	187.2×	0.009	HPCA
regulation of signal transduction	1	133.8×	0.011	HPCA
retina development in camera-type eye	1	127.7×	0.011	HPCA
calcium ion transmembrane transport	1	105.3×	0.012	CACNA1A
cellular response to calcium ion	1	100.3×	0.012	HPCA
calcium-mediated signaling	1	91.6×	0.012	HPCA
modulation of chemical synaptic transmission	1	91.6×	0.012	CACNA1A
positive regulation of cytosolic calcium ion concentration	1	58.5×	0.018	CACNA1A
chemical synaptic transmission	1	38.6×	0.026	CACNA1A

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
CACNA1A	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1A	2	4
HPCA	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNA1A	19	Binding:18, Functional:1

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

2 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)
NIMODIPINE	4	CACNA1A
TACRINE	4	CACNA1A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	CACNA1A
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	HPCA

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)
HPCA	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.