Episodic ataxia type 1

Summary

Episodic ataxia type 1 (MONDO:0008047) is a disease caused by KCNA1 (GenCC Definitive), with 2 cohort genes and 1 clinical trial.

At a glance

• Prevalence: Unknown (Worldwide)
• Causal gene: KCNA1 (GenCC Definitive)
• Cohort genes: 2
• ClinVar variants: 638
• Phenotypes (HPO): 27
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

27 HPO clinical features (Orphanet curated; top 27 by frequency):

HPO ID	Term	Frequency
HP:0002172	Postural instability	Very frequent (80-99%)
HP:0002370	Poor coordination	Very frequent (80-99%)
HP:0002411	Myokymia	Very frequent (80-99%)
HP:0000622	Blurred vision	Frequent (30-79%)
HP:0000651	Diplopia	Frequent (30-79%)
HP:0000975	Hyperhidrosis	Frequent (30-79%)
HP:0001260	Dysarthria	Frequent (30-79%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0002312	Clumsiness	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002321	Vertigo	Frequent (30-79%)
HP:0003394	Muscle spasm	Frequent (30-79%)
HP:0003552	Muscle stiffness	Frequent (30-79%)
HP:0000750	Delayed speech and language development	Occasional (5-29%)
HP:0001188	Hand clenching	Occasional (5-29%)
HP:0001266	Choreoathetosis	Occasional (5-29%)
HP:0001270	Motor delay	Occasional (5-29%)
HP:0001272	Cerebellar atrophy	Occasional (5-29%)
HP:0001276	Hypertonia	Occasional (5-29%)
HP:0001328	Specific learning disability	Occasional (5-29%)
HP:0002098	Respiratory distress	Occasional (5-29%)
HP:0002486	Myotonia	Occasional (5-29%)
HP:0002650	Scoliosis	Occasional (5-29%)
HP:0002751	Kyphoscoliosis	Occasional (5-29%)
HP:0005461	Craniofacial disproportion	Occasional (5-29%)
HP:0008981	Calf muscle hypertrophy	Occasional (5-29%)
HP:0030051	Tip-toe gait	Occasional (5-29%)

Identifiers

Disease identifiers

Field	Value
Canonical name	episodic ataxia type 1
Mondo ID	MONDO:0008047
OMIM	160120
Orphanet	37612
DOID	DOID:0050989
SNOMED CT	421182009
UMLS	C1719788
MedGen	318554
GARD	0016641
Is cancer (heuristic)	no

Also known as: acetazolamide-responsive periodic ataxia · ataxia, episodic, with myokymia · continuous muscle fiber activity · EA1 · episodic ataxia with myokymia · episodic ataxia, type 1 · episodic ataxia/myokymia syndrome · familial paroxysmal kinesigenic ataxia and continuous myokymia · hereditary episodic ataxia caused by mutation in KCNA1 · hereditary paroxysmal ataxia with neuromyotonia · Isaacs-Mertens syndrome · KCNA1 hereditary episodic ataxia · myokymia with episodic ataxia · myokymia with periodic ataxia · paroxysmal ataxia with neuromyotonia, hereditary

Data availability: 638 ClinVar variants · 4 GenCC gene-disease records · 6 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 1

Related subtypes (8): episodic ataxia type 2, 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:

323 uncertain significance, 168 likely benign, 37 benign, 20 benign/likely benign, 19 pathogenic, 18 conflicting classifications of pathogenicity, 12 likely pathogenic, 3 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
1098714	NM_000217.3(KCNA1):c.1187G>T (p.Gly396Val)	KCNA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
13480	NM_000217.3(KCNA1):c.1223T>C (p.Val408Ala)	KCNA1	Pathogenic	no assertion criteria provided
13481	NM_000217.3(KCNA1):c.715C>A (p.Arg239Ser)	KCNA1	Pathogenic	no assertion criteria provided
13482	NM_000217.3(KCNA1):c.520G>T (p.Val174Phe)	KCNA1	Pathogenic	criteria provided, multiple submitters, no conflicts
13483	NM_000217.3(KCNA1):c.745T>A (p.Phe249Ile)	KCNA1	Pathogenic	criteria provided, single submitter
13484	NM_000217.3(KCNA1):c.551T>G (p.Phe184Cys)	KCNA1	Pathogenic	no assertion criteria provided
13485	NM_000217.3(KCNA1):c.975G>C (p.Glu325Asp)	KCNA1	Pathogenic	no assertion criteria provided
13486	NM_000217.3(KCNA1):c.676A>G (p.Thr226Ala)	KCNA1	Pathogenic	criteria provided, single submitter
13487	NM_000217.3(KCNA1):c.1210G>A (p.Val404Ile)	KCNA1	Pathogenic	criteria provided, multiple submitters, no conflicts
13488	NM_000217.3(KCNA1):c.530T>A (p.Ile177Asn)	KCNA1	Pathogenic	no assertion criteria provided
13491	NM_000217.3(KCNA1):c.1249C>T (p.Arg417Ter)	KCNA1	Pathogenic	criteria provided, multiple submitters, no conflicts
13492	NM_000217.3(KCNA1):c.677C>G (p.Thr226Arg)	KCNA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1411967	NM_000217.3(KCNA1):c.1126G>A (p.Gly376Ser)	KCNA1	Pathogenic	criteria provided, single submitter
1452721	NM_000217.3(KCNA1):c.850C>T (p.Gln284Ter)	KCNA1	Pathogenic	criteria provided, single submitter
1697293	NM_000217.3(KCNA1):c.847G>A (p.Glu283Lys)	KCNA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1698514	NM_000217.3(KCNA1):c.785T>C (p.Ile262Thr)	KCNA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
21127	NM_000217.3(KCNA1):c.677C>T (p.Thr226Met)	KCNA1	Pathogenic	criteria provided, multiple submitters, no conflicts
2236795	NM_000217.3(KCNA1):c.745TTC[1] (p.Phe250del)	KCNA1	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
2500186	NM_000217.3(KCNA1):c.1102G>C (p.Val368Leu)	KCNA1	Pathogenic	criteria provided, single submitter
2910304	NM_000217.3(KCNA1):c.1207C>T (p.Pro403Ser)	KCNA1	Pathogenic	criteria provided, single submitter
4057247	NM_000217.3(KCNA1):c.941T>A (p.Ile314Asn)	KCNA1	Pathogenic	no assertion criteria provided
447609	NM_000217.3(KCNA1):c.1214C>T (p.Pro405Leu)	KCNA1	Pathogenic	criteria provided, multiple submitters, no conflicts
1805796	NM_000217.3(KCNA1):c.985C>A (p.Leu329Ile)	KCNA1	Likely pathogenic	criteria provided, single submitter
1994858	NM_000217.3(KCNA1):c.985C>T (p.Leu329Phe)	KCNA1	Likely pathogenic	criteria provided, single submitter
2576584	NM_000217.3(KCNA1):c.863T>A (p.Leu288Gln)	KCNA1	Likely pathogenic	criteria provided, single submitter
2577881	NM_000217.3(KCNA1):c.966T>A (p.Ser322Arg)	KCNA1	Likely pathogenic	criteria provided, single submitter
2759454	NM_000217.3(KCNA1):c.974A>G (p.Glu325Gly)	KCNA1	Likely pathogenic	criteria provided, single submitter
3378412	NM_000217.3(KCNA1):c.730C>T (p.Pro244Ser)	KCNA1	Likely pathogenic	criteria provided, single submitter
3382352	NM_000217.3(KCNA1):c.1226C>A (p.Ser409Tyr)	KCNA1	Likely pathogenic	criteria provided, single submitter
3778752	NM_000217.3(KCNA1):c.1241T>C (p.Phe414Ser)	KCNA1	Likely pathogenic	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 10 · Orphanet: 6 · 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
KCNA1	Definitive	Autosomal dominant	episodic ataxia type 1	10

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
KCNA1	Orphanet:1934	Early infantile developmental and epileptic encephalopathy
KCNA1	Orphanet:199326	Isolated autosomal dominant hypomagnesemia, Glaudemans type
KCNA1	Orphanet:37612	Episodic ataxia type 1
KCNA1	Orphanet:972	Hereditary continuous muscle fiber activity
KCNA1	Orphanet:98809	Paroxysmal kinesigenic dyskinesia
AKAP3	Orphanet:137893	Male infertility due to large-headed multiflagellar polyploid spermatozoa

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
KCNA1	HGNC:6218	ENSG00000111262	Q09470	Potassium voltage-gated channel subfamily A member 1	gencc,clinvar
AKAP3	HGNC:373	ENSG00000111254	O75969	A-kinase anchor protein 3	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
KCNA1	Potassium voltage-gated channel subfamily A member 1	Voltage-gated potassium channel that mediates transmembrane potassium transport in excitable membranes, primarily in the brain and the central nervous system, but also in the kidney.
AKAP3	A-kinase anchor protein 3	Structural component of sperm fibrous sheath.

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)
KCNA1	Ion channel	yes		BTB/POZ_dom, T1-type_BTB, K_chnl_volt-dep_Kv
AKAP3	Other/Unknown	no		SPHK1-interactor_AKAP_110, AKAP_110_C, AKAP_110

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
Brodmann (1909) area 23	1
endothelial cell	1
middle temporal gyrus	1
left testis	1
right testis	1
testis	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
KCNA1	151	broad	marker	endothelial cell, Brodmann (1909) area 23, middle temporal gyrus
AKAP3	170	broad	marker	left testis, right testis, testis

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
KCNA1	3,157
AKAP3	1,013

Structural data

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

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
KCNA1	Q09470	78.74
AKAP3	O75969	50.79

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 3. 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
Voltage gated Potassium channels	1	243.0×	0.011	KCNA1
Potassium Channels	1	134.3×	0.011	KCNA1
Neuronal System	1	44.3×	0.023	KCNA1

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
cell communication by electrical coupling	1	2106.5×	0.004	KCNA1
detection of mechanical stimulus involved in sensory perception of touch	1	2106.5×	0.004	KCNA1
neuronal signal transduction	1	1203.7×	0.004	KCNA1
cellular response to magnesium ion	1	1203.7×	0.004	KCNA1
magnesium ion homeostasis	1	936.2×	0.004	KCNA1
regulation of muscle contraction	1	842.6×	0.004	KCNA1
membrane repolarization during action potential	1	842.6×	0.004	KCNA1
startle response	1	561.7×	0.005	KCNA1
detection of mechanical stimulus involved in sensory perception of pain	1	561.7×	0.005	KCNA1
acrosome reaction	1	443.5×	0.005	AKAP3
cell surface receptor protein serine/threonine kinase signaling pathway	1	366.4×	0.006	AKAP3
blastocyst hatching	1	271.8×	0.007	AKAP3
neuromuscular process	1	263.3×	0.007	KCNA1
neuronal action potential	1	240.7×	0.007	KCNA1
establishment of protein localization	1	216.1×	0.007	AKAP3
neuroblast proliferation	1	183.2×	0.008	KCNA1
action potential	1	179.3×	0.008	KCNA1
hippocampus development	1	115.4×	0.011	KCNA1
regulation of membrane potential	1	115.4×	0.011	KCNA1
single fertilization	1	91.6×	0.013	AKAP3
potassium ion transmembrane transport	1	68.0×	0.017	KCNA1
protein homooligomerization	1	61.1×	0.018	KCNA1
flagellated sperm motility	1	58.5×	0.018	AKAP3
intracellular protein localization	1	52.3×	0.019	AKAP3

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
KCNA1	NIFEDIPINE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
KCNA1	5	4
AKAP3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
NIFEDIPINE	4	KCNA1
DALFAMPRIDINE	4	KCNA1
CAPSAICIN	4	KCNA1
CORTISONE	3	KCNA1
TETRYLAMMONIUM	2	KCNA1

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
KCNA1	59	Binding:52, Functional:6, Toxicity: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

5 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)
NIFEDIPINE	4	KCNA1
DALFAMPRIDINE	4	KCNA1
CAPSAICIN	4	KCNA1
CORTISONE	3	KCNA1
TETRYLAMMONIUM	2	KCNA1

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	KCNA1
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	AKAP3

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)
AKAP3	0	—

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
NCT01793168	Not specified	RECRUITING	Rare Disease Patient Registry & Natural History Study - Coordination of Rare Diseases at Sanford