Episodic ataxia type 2

Summary

Episodic ataxia type 2 (MONDO:0007163) is a disease caused by CACNA1A (GenCC Definitive), with 4 cohort genes and 2 clinical trials. Top therapeutic interventions include dalfampridine and levacetylleucine.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: CACNA1A (GenCC Definitive)
• Cohort genes: 4
• ClinVar variants: 3,114
• Phenotypes (HPO): 14
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 1 000 000		United States	Not yet validated

Signs & symptoms

Clinical features (HPO)

14 HPO clinical features (Orphanet curated; top 14 by frequency):

HPO ID	Term	Frequency
HP:0000639	Nystagmus	Very frequent (80-99%)
HP:0001251	Ataxia	Very frequent (80-99%)
HP:0002321	Vertigo	Very frequent (80-99%)
HP:0000360	Tinnitus	Frequent (30-79%)
HP:0000651	Diplopia	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0001332	Dystonia	Frequent (30-79%)
HP:0002017	Nausea and vomiting	Frequent (30-79%)
HP:0002076	Migraine	Frequent (30-79%)
HP:0002301	Hemiplegia	Frequent (30-79%)
HP:0000473	Torticollis	Occasional (5-29%)
HP:0000708	Atypical behavior	Occasional (5-29%)
HP:0001249	Intellectual disability	Occasional (5-29%)
HP:0006855	Cerebellar vermis atrophy	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	episodic ataxia type 2
Mondo ID	MONDO:0007163
MeSH	C535506
OMIM	108500
Orphanet	97
DOID	DOID:0050990
SNOMED CT	420932006
UMLS	C1720416
MedGen	314039
GARD	0009602
Is cancer (heuristic)	no

Also known as: Acetazolamide-responsive episodic ataxia syndrome · Acetazolamide-responsive, hereditary, paroxysmal, cerebellar ataxia · APCA · ataxia, familial, paroxysmal · CACNA1A hereditary episodic ataxia · CAPA · EA2 · episodic ataxia type 2 · episodic ataxia with nystagmus · episodic ataxia, type 2 · hereditary episodic ataxia caused by mutation in CACNA1A · Nystagmus-associated episodic ataxia

Data availability: 3,114 ClinVar variants · 4 GenCC gene-disease records · 4 cell lines.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › atactic disorder › hereditary ataxia › hereditary episodic ataxia › episodic ataxia type 2

Related subtypes (8): episodic ataxia type 1, episodic ataxia type 4, episodic ataxia type 3, episodic ataxia type 7, episodic ataxia type 6, episodic ataxia type 5, episodic ataxia type 8, episodic ataxia, type 9

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

600 retrieved; paginated sample, class counts are floors:

248 uncertain significance, 197 likely benign, 56 conflicting classifications of pathogenicity, 42 pathogenic, 28 benign, 15 likely pathogenic, 8 benign/likely benign, 6 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1011068	NM_001127222.2(CACNA1A):c.4324T>G (p.Tyr1442Asp)	CACNA1A	Pathogenic	criteria provided, single submitter
1027685	NM_001127222.2(CACNA1A):c.3039C>G (p.Tyr1013Ter)	CACNA1A	Pathogenic	criteria provided, single submitter
1027687	NM_001127222.2(CACNA1A):c.826G>T (p.Glu276Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1033712	NM_001127222.2(CACNA1A):c.2482C>T (p.Gln828Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1051890	NM_001127222.2(CACNA1A):c.1882G>A (p.Ala628Thr)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1068487	NM_001127222.2(CACNA1A):c.4514T>C (p.Phe1505Ser)	CACNA1A	Pathogenic	criteria provided, single submitter
1070324	NM_001127222.2(CACNA1A):c.3563del (p.Asn1188fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1070484	NC_000019.9:g.(?13338225)(13342694_?)del	CACNA1A	Pathogenic	criteria provided, single submitter
1072305	NM_001127222.2(CACNA1A):c.6397_6403del (p.Arg2133fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1074371	NM_001127222.2(CACNA1A):c.4085del (p.Leu1362fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1074784	NM_001127222.2(CACNA1A):c.2401G>T (p.Glu801Ter)	CACNA1A	Pathogenic	criteria provided, single submitter
1075147	NM_001127222.2(CACNA1A):c.6371C>A (p.Ser2124Ter)	CACNA1A	Pathogenic	criteria provided, single submitter
1075289	NM_001127222.2(CACNA1A):c.4795del (p.Val1599fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1075959	NM_001127222.2(CACNA1A):c.3006_3007delinsCT (p.Arg1002_Arg1003delinsSerTer)	CACNA1A	Pathogenic	criteria provided, single submitter
1076899	NM_001127221.2(CACNA1A):c.5588_5589del (p.Leu1863fs)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1204133	NM_001127222.2(CACNA1A):c.4403C>T (p.Ser1468Leu)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1207431	NM_001127222.2(CACNA1A):c.605C>T (p.Pro202Leu)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1303894	NM_001127222.2(CACNA1A):c.2026G>A (p.Gly676Arg)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1334375	NM_001127222.2(CACNA1A):c.526del (p.Val176fs)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1338921	NM_001127222.2(CACNA1A):c.5335C>T (p.Arg1779Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1366064	NC_000019.9:g.(?13427906)(13617038_?)del	CACNA1A	Pathogenic	criteria provided, single submitter
1373236	NM_001127222.2(CACNA1A):c.2840del (p.Pro947fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1374639	NM_001127222.2(CACNA1A):c.507G>A (p.Trp169Ter)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1376008	NM_001127222.2(CACNA1A):c.876dup (p.Gly293fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1377252	NM_001127222.2(CACNA1A):c.5477dup (p.His1826fs)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1382040	NM_001127222.2(CACNA1A):c.3838_3841del (p.Asp1280fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1387896	NM_001127222.2(CACNA1A):c.3277_3283del (p.Ser1093fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1395073	NM_001127222.2(CACNA1A):c.110_125dup (p.Gly43fs)	CACNA1A	Pathogenic	criteria provided, single submitter
1398258	NM_001127222.2(CACNA1A):c.841del (p.Cys281fs)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
1401261	NM_001127222.2(CACNA1A):c.4366del (p.Ser1456fs)	CACNA1A	Pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 23 · 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	Definitive	Autosomal dominant	episodic ataxia type 2	23

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
ACP5	Orphanet:1855	Spondyloenchondrodysplasia

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
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	gencc,clinvar
ACP5	HGNC:124	ENSG00000102575	P13686	Tartrate-resistant acid phosphatase type 5	clinvar
BEST2	HGNC:17107	ENSG00000039987	Q8NFU1	Bestrophin-2a	clinvar
WDR83OS	HGNC:30203	ENSG00000105583	Q9Y284	PAT complex subunit Asterix	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…
ACP5	Tartrate-resistant acid phosphatase type 5	Involved in osteopontin/bone sialoprotein dephosphorylation.
BEST2	Bestrophin-2a	Ligand-gated anion channel that allows the movement of anions across cell membranes when activated by calcium (Ca2+).
WDR83OS	PAT complex subunit Asterix	Component of the multi-pass translocon (MPT) complex that mediates insertion of multi-pass membrane proteins into the lipid bilayer of membranes.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 2 · 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	27.9×	0.106
Enzyme (other)	1	3.0×	0.441
Other/Unknown	2	0.9×	0.769

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
ACP5	Enzyme (other)	yes	3.1.3.2	Calcineurin-like_PHP, Acid_PPase, Metallo-depent_PP-like
BEST2	Other/Unknown	no		Bestrophin, Bestrophin-like
WDR83OS	Other/Unknown	no		ASTER

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
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
periodontal ligament	1
right lung	1
upper lobe of left lung	1
mucosa of sigmoid colon	1
mucosa of transverse colon	1
transverse colon	1
fallopian tube	1
pituitary gland	1
right adrenal gland	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
ACP5	233	broad	marker	periodontal ligament, upper lobe of left lung, right lung
BEST2	153	tissue_specific	marker	mucosa of transverse colon, transverse colon, mucosa of sigmoid colon
WDR83OS	134	ubiquitous	marker	right adrenal gland, pituitary gland, fallopian tube

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ACP5	2,983
WDR83OS	979
BEST2	584
CACNA1A	346

Structural data

PDB: 3 · AlphaFold-only: 1 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
BEST2	Q8NFU1	10
CACNA1A	O00555	4
ACP5	P13686	2

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
WDR83OS	Q9Y284	62.09

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 4 evidence-associated genes (3 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 3 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Vitamin B2 (riboflavin) metabolism	1	543.8×	0.016	ACP5
Presynaptic depolarization and calcium channel opening	1	317.2×	0.016	CACNA1A
Regulation of insulin secretion	1	73.2×	0.042	CACNA1A
Integration of energy metabolism	1	58.6×	0.042	CACNA1A
Stimuli-sensing channels	1	45.3×	0.044	BEST2
Ion channel transport	1	32.0×	0.052	BEST2
Transmission across Chemical Synapses	1	25.4×	0.056	CACNA1A
Neuronal System	1	14.8×	0.083	CACNA1A
Transport of small molecules	1	8.4×	0.127	BEST2
Metabolism	1	3.9×	0.237	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 4 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
negative regulation of superoxide anion generation	1	2106.5×	0.012	ACP5
multi-pass transmembrane protein insertion into ER membrane	1	468.1×	0.015	WDR83OS
protein insertion into ER membrane	1	383.0×	0.015	WDR83OS
negative regulation of macrophage cytokine production	1	300.9×	0.015	ACP5
negative regulation of interleukin-12 production	1	263.3×	0.015	ACP5
negative regulation of nitric oxide biosynthetic process	1	247.8×	0.015	ACP5
response to amyloid-beta	1	247.8×	0.015	CACNA1A
nitric oxide biosynthetic process	1	175.5×	0.015	ACP5
superoxide anion generation	1	168.5×	0.015	ACP5
bone morphogenesis	1	150.5×	0.015	ACP5
bone resorption	1	145.3×	0.015	ACP5
calcium ion import across plasma membrane	1	135.9×	0.015	CACNA1A
negative regulation of interleukin-1 beta production	1	127.7×	0.015	ACP5
membrane depolarization	1	127.7×	0.015	BEST2
cellular response to amyloid-beta	1	98.0×	0.017	CACNA1A
response to cytokine	1	93.6×	0.017	ACP5
negative regulation of tumor necrosis factor production	1	62.9×	0.024	ACP5
chloride transmembrane transport	1	59.3×	0.024	BEST2
calcium ion transmembrane transport	1	52.7×	0.026	CACNA1A
modulation of chemical synaptic transmission	1	45.8×	0.028	CACNA1A
sensory perception of smell	1	39.0×	0.031	BEST2
negative regulation of inflammatory response	1	34.2×	0.034	ACP5
defense response to Gram-positive bacterium	1	31.9×	0.034	ACP5
response to lipopolysaccharide	1	31.2×	0.034	ACP5
positive regulation of cytosolic calcium ion concentration	1	29.3×	0.035	CACNA1A
chemical synaptic transmission	1	19.3×	0.051	CACNA1A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 4 evidence-associated genes (25%) 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
ACP5	0	0
BEST2	0	0
WDR83OS	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): 1.

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

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

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ACP5	3.1.3.2	acid phosphatase

Pharmacogenomics

Cohort genes with a PharmGKB record: 4; 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	1	ACP5
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	2	BEST2, WDR83OS

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
ACP5	0	—
BEST2	0	—
WDR83OS	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 2.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT07221292	PHASE3	NOT_YET_RECRUITING	Pivotal Study of N-acetyl-L-leucine for CACNA1A
NCT01543750	PHASE2	WITHDRAWN	4-Aminopyridine in Episodic Ataxia Type 2

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DALFAMPRIDINE	4	1
LEVACETYLLEUCINE	4	1