Hereditary episodic ataxia

Summary

Hereditary episodic ataxia (MONDO:0016227) is a disease (an umbrella term covering 9 Mondo subtypes) with 5 cohort genes and 2 clinical trials.

At a glance

• Prevalence: 1-9 / 100 000 (Worldwide)
• Umbrella term: 9 Mondo subtypes
• Cohort genes: 5
• ClinVar variants: 8
• Clinical trials: 2

Clinical features

Epidemiology

Prevalence records

1 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000		Worldwide	Not yet validated

Identifiers

Disease identifiers

Field	Value
Canonical name	hereditary episodic ataxia
Mondo ID	MONDO:0016227
OMIM	160120
Orphanet	211062
DOID	DOID:963
ICD-11	423095680
SNOMED CT	421455009
UMLS	C1720189
MedGen	314033
GARD	0020457
Is cancer (heuristic)	no

Also known as: ea syndrome · episodic ataxia · episodic ataxia syndrome

Data availability: 8 ClinVar variants · 1 GenCC gene-disease record.

Disease family

An umbrella term covering 9 Mondo subtypes.

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

Related subtypes (19): ataxia with fasciculations, muscular atrophy-ataxia-retinitis pigmentosa-diabetes mellitus syndrome, myoclonus-cerebellar ataxia-deafness syndrome, cataract-ataxia-deafness syndrome, ataxia-hypogonadism-choroidal dystrophy syndrome, ichthyosis-hepatosplenomegaly-cerebellar degeneration syndrome, Richards-Rundle syndrome, spinocerebellar ataxia-dysmorphism syndrome, ataxia-tapetoretinal degeneration syndrome, hereditary spastic paraplegia 7, autosomal dominant sensory ataxia 1, EAST syndrome, juvenile-onset diabetes mellitus-central and peripheral neurodegeneration syndrome, severe microbrachycephaly-intellectual disability-athetoid cerebral palsy syndrome, spastic ataxia, tremor-ataxia-central hypomyelination syndrome, hereditary cerebellar ataxia, autosomal recessive ataxia due to PEX16 deficiency, autosomal recessive ataxia due to PEX2 deficiency

Subtypes (9): episodic ataxia type 2, 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

8 retrieved; paginated sample, class counts are floors:

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

ClinVar	Variant (HGVS)	Gene	Classification	Review
1454996	NM_001127222.2(CACNA1A):c.815G>A (p.Cys272Tyr)	CACNA1A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
3769351	NC_000019.9:g.(?13317255)(13387943_13394080)del	CACNA1A	Pathogenic	criteria provided, single submitter
68421	NM_001127222.2(CACNA1A):c.1499C>T (p.Thr500Met)	CACNA1A	Pathogenic	criteria provided, multiple submitters, no conflicts
206978	NM_001040142.2(SCN2A):c.2960G>T (p.Ser987Ile)	SCN2A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
812930	NC_000022.11:g.20042177_20075233del	TANGO2	Pathogenic	no assertion criteria provided
935554	NM_001127222.2(CACNA1A):c.5248C>T (p.Arg1750Trp)	CACNA1A	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
983126	NM_138420.4(AHNAK2):c.6406_6408delinsGAC (p.Gln2136Asp)	AHNAK2	Uncertain significance	criteria provided, single submitter
560369	NM_001127222.2(CACNA1A):c.6689A>G (p.Gln2230Arg)	CACNA1A	Uncertain significance	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 1 · Orphanet: 16 · 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
UBR4	Moderate	Autosomal dominant	hereditary episodic ataxia

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN2A	Orphanet:140927	Self-limited neonatal-infantile epilepsy
SCN2A	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
SCN2A	Orphanet:2131	Alternating hemiplegia of childhood
SCN2A	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
SCN2A	Orphanet:306	Self-limited infantile epilepsy
SCN2A	Orphanet:33069	Dravet syndrome
SCN2A	Orphanet:36387	Genetic epilepsy with febrile seizure plus
SCN2A	Orphanet:697160	Infantile epileptic spasms syndrome
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
TANGO2	Orphanet:480864	Recurrent metabolic encephalomyopathic crises-rhabdomyolysis-cardiac arrhythmia-intellectual disability syndrome

Cohort genes → proteins

5 cohort genes, 5 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	5

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
UBR4	HGNC:30313	ENSG00000127481	Q5T4S7	E3 ubiquitin-protein ligase UBR4	gencc
SCN2A	HGNC:10588	ENSG00000136531	Q99250	Sodium channel protein type 2 subunit alpha	clinvar
CACNA1A	HGNC:1388	ENSG00000141837	O00555	Voltage-dependent P/Q-type calcium channel subunit alpha-1A	clinvar
AHNAK2	HGNC:20125	ENSG00000185567	Q8IVF2	Protein AHNAK2	clinvar
TANGO2	HGNC:25439	ENSG00000183597	Q6ICL3	Transport and Golgi organization protein 2 homolog	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
UBR4	E3 ubiquitin-protein ligase UBR4	E3 ubiquitin-protein ligase involved in different protein quality control pathways in the cytoplasm.
SCN2A	Sodium channel protein type 2 subunit alpha	Mediates the voltage-dependent sodium ion permeability of excitable membranes.
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…
TANGO2	Transport and Golgi organization protein 2 homolog	May be involved in lipid homeostasis.

Protein-family classification

Druggable: 2 · Difficult: 2 · Unknown: 1 · 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
Ion channel	2	44.6×	0.003
Scaffold/PPI	1	3.5×	0.515
Transcription factor	1	1.6×	0.634
Other/Unknown	1	0.4×	0.983

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
UBR4	Transcription factor	no		Znf_UBR, ARM-type_fold, E3_Ub_ligase_UBR4_C
SCN2A	Ion channel	yes		IQ_motif_EF-hand-BS, Na_channel_asu, Ion_trans_dom
CACNA1A	Ion channel	yes		VDCCAlpha1, CACNA1A, Ion_trans_dom
AHNAK2	Scaffold/PPI	no		PDZ, PDZ_sf, Myelin_sheath_structural
TANGO2	Other/Unknown	no		TANGO2

Expression context

Cohort genes with no expression data: 0.

5 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
right testis	1
skin of abdomen	1
skin of leg	1
Brodmann (1909) area 23	1
cerebellar vermis	1
middle temporal gyrus	1
cerebellar cortex	1
cerebellar hemisphere	1
right hemisphere of cerebellum	1
gingival epithelium	1
tendon of biceps brachii	1
upper leg skin	1
apex of heart	1
blood	1
granulocyte	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
UBR4	175	ubiquitous	marker	skin of leg, skin of abdomen, right testis
SCN2A	187	broad	marker	middle temporal gyrus, Brodmann (1909) area 23, cerebellar vermis
CACNA1A	237	broad	marker	cerebellar hemisphere, right hemisphere of cerebellum, cerebellar cortex
AHNAK2	254	ubiquitous	marker	tendon of biceps brachii, upper leg skin, gingival epithelium
TANGO2	217	ubiquitous	marker	apex of heart, granulocyte, blood

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
AHNAK2	2,819
SCN2A	2,810
UBR4	2,517
TANGO2	831
CACNA1A	346

Structural data

PDB: 5 · AlphaFold-only: 0 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
UBR4	Q5T4S7	13
SCN2A	Q99250	5
CACNA1A	O00555	4
TANGO2	Q6ICL3	3
AHNAK2	Q8IVF2	1

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 20. Enrichment computed across 5 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
Presynaptic depolarization and calcium channel opening	1	317.2×	0.036	CACNA1A
Interaction between L1 and Ankyrins	1	122.8×	0.036	SCN2A
Phase 0 - rapid depolarisation	1	115.3×	0.036	SCN2A
Sensory perception of taste	1	112.0×	0.036	SCN2A
Dengue virus activates/modulates innate and adaptive immune responses	1	112.0×	0.036	UBR4
Sensory perception of sweet, bitter, and umami (glutamate) taste	1	92.8×	0.036	SCN2A
Regulation of insulin secretion	1	73.2×	0.039	CACNA1A
Integration of energy metabolism	1	58.6×	0.042	CACNA1A
L1CAM interactions	1	40.1×	0.055	SCN2A
Cardiac conduction	1	36.2×	0.055	SCN2A
Sensory Perception	1	31.7×	0.057	SCN2A
Muscle contraction	1	25.7×	0.060	SCN2A
Transmission across Chemical Synapses	1	25.4×	0.060	CACNA1A
Axon guidance	1	15.1×	0.085	SCN2A
Neuronal System	1	14.8×	0.085	CACNA1A
Nervous system development	1	14.3×	0.085	SCN2A
Antigen processing: Ubiquitination & Proteasome degradation	1	12.4×	0.092	UBR4
Neutrophil degranulation	1	7.7×	0.138	UBR4
Developmental Biology	1	4.8×	0.204	SCN2A
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 5 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
intrinsic apoptotic signaling pathway in response to osmotic stress	1	1685.2×	0.008	SCN2A
negative regulation of HRI-mediated signaling	1	1685.2×	0.008	UBR4
cytoplasm protein quality control by the ubiquitin-proteasome system	1	1123.5×	0.008	UBR4
cytoplasm protein quality control	1	1123.5×	0.008	UBR4
ubiquitin-dependent protein catabolic process via the N-end rule pathway	1	674.1×	0.011	UBR4
protein K27-linked ubiquitination	1	240.7×	0.023	UBR4
response to amyloid-beta	1	198.3×	0.023	CACNA1A
negative regulation of fatty acid biosynthetic process	1	177.4×	0.023	UBR4
protein branched polyubiquitination	1	168.5×	0.023	UBR4
protein quality control for misfolded or incompletely synthesized proteins	1	153.2×	0.023	UBR4
cardiac muscle cell action potential involved in contraction	1	140.4×	0.023	SCN2A
calcium ion import across plasma membrane	1	108.7×	0.027	CACNA1A
neuronal action potential	1	96.3×	0.029	SCN2A
protein K11-linked ubiquitination	1	78.4×	0.030	UBR4
cellular response to amyloid-beta	1	78.4×	0.030	CACNA1A
endosome organization	1	74.9×	0.030	UBR4
sodium ion transport	1	54.4×	0.037	SCN2A
protein secretion	1	52.7×	0.037	TANGO2
myelination	1	50.3×	0.037	SCN2A
regulation of RNA splicing	1	43.8×	0.037	AHNAK2
calcium ion transmembrane transport	1	42.1×	0.037	CACNA1A
positive regulation of autophagy	1	41.6×	0.037	UBR4
sodium ion transmembrane transport	1	40.6×	0.037	SCN2A
neuron apoptotic process	1	37.0×	0.037	SCN2A
memory	1	36.6×	0.037	SCN2A
modulation of chemical synaptic transmission	1	36.6×	0.037	CACNA1A
protein K48-linked ubiquitination	1	33.7×	0.039	UBR4
Golgi organization	1	26.8×	0.047	TANGO2
response to oxidative stress	1	26.1×	0.047	UBR4
cellular response to hypoxia	1	24.2×	0.049	SCN2A

Therapeutics

Drug target analysis

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

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
SCN2A	BEPRIDIL
CACNA1A	NIMODIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN2A	99	4
CACNA1A	2	4
UBR4	0	0
AHNAK2	0	0
TANGO2	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	SCN2A
ETIDOCAINE	4	SCN2A
CHLORPHENIRAMINE	4	SCN2A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN2A	203	Binding:172, Functional:20, ADMET:10, Toxicity:1
CACNA1A	19	Binding:18, Functional:1
UBR4	11	Binding:11

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
SCN2A	203

Pharmacogenomics

Cohort genes with a PharmGKB record: 5; 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)
BEPRIDIL	4	SCN2A
DIBUCAINE	4	SCN2A
ARTICAINE	4	SCN2A
BUPIVACAINE	4	SCN2A
IMIPRAMINE	4	SCN2A
DROPERIDOL	4	SCN2A
DICYCLOMINE	4	SCN2A
TETRABENAZINE	4	SCN2A
PHENIRAMINE	4	SCN2A
PRILOCAINE	4	SCN2A
PROPOXYCAINE	4	SCN2A
PROPARACAINE	4	SCN2A
HEXYLCAINE	4	SCN2A
PRAMOXINE	4	SCN2A
BENOXINATE	4	SCN2A
QUINIDINE	4	SCN2A
FELODIPINE	4	SCN2A
PHENYTOIN	4	SCN2A
QUININE	4	SCN2A
NISOLDIPINE	4	SCN2A
NIFEDIPINE	4	SCN2A
PRAZOSIN	4	SCN2A
DILTIAZEM	4	SCN2A
PRENYLAMINE	4	SCN2A
COCAINE	4	SCN2A
TRIFLUOPERAZINE	4	SCN2A
CINNARIZINE	4	SCN2A
THIORIDAZINE	4	SCN2A
ETIDOCAINE	4	SCN2A
CHLORPHENIRAMINE	4	SCN2A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SCN2A, 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	3	UBR4, AHNAK2, TANGO2

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)
UBR4	11	—
AHNAK2	0	—
TANGO2	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
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford
NCT00266760	Not specified	COMPLETED	Characteristics of Episodic Ataxia Syndrome