Periodic paralysis

Summary

Periodic paralysis (MONDO:0016122) is a disease with 3 cohort genes.

At a glance

• Cohort genes: 3
• ClinVar variants: 3

Clinical features

No curated clinical features (Orphanet) for this disease.

Identifiers

Disease identifiers

Field	Value
Canonical name	periodic paralysis
Mondo ID	MONDO:0016122
Orphanet	206976
ICD-10-CM	G72.3
ICD-11	577112387
UMLS	C1279412
MedGen	488958
GARD	0020374
MedDRA	10016208
Is cancer (heuristic)	no

Also known as: periodic paralysis · periodic paralysis (disease)

Data availability: 3 ClinVar variants · 1 HPO phenotype.

Disease family

An umbrella term covering 1 Mondo subtype.

Classification path: disease › human disease › disease by body system or component › nervous system disorder › periodic paralysis

Related subtypes (71): congenital nervous system disorder, central nervous system disorder, autoimmune disorder of the nervous system, cranial nerve neuropathy, peripheral nervous system disorder, neuronitis, diplegia of upper limb, retinal disorder, developmental disability, restless legs syndrome, movement disorder, toxic encephalopathy, Barre-Lieou syndrome, Gerstmann syndrome, drug-induced akathisia, drug-induced dyskinesia, stiff-person syndrome, Worster-Drought syndrome, corneal-cerebellar syndrome, pachygyria-intellectual disability-epilepsy syndrome, porencephaly-cerebellar hypoplasia-internal malformations syndrome, symmetrical thalamic calcifications, neonatal brainstem dysfunction, primary orthostatic hypotension, rippling muscle disease with myasthenia gravis, qualitative or quantitative protein defects in neuromuscular diseases, specific learning disability, cerebellar hypoplasia-tapetoretinal degeneration syndrome, locked-in syndrome, dopa-responsive dystonia, idiopathic recurrent stupor, chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids, spontaneous periodic hypothermia, Sydenham chorea, duplication of the pituitary gland, Balint syndrome, paraneoplastic neurologic syndrome, persistent idiopathic facial pain, serotonin syndrome, hypothalamic adipsic hypernatraemia syndrome, exercise-induced malignant hyperthermia, perineural cyst, neuromuscular disease, neuromyelitis optica, AL amyloidosis, AA amyloidosis, neuroleptic malignant syndrome, infectious disorder of the nervous system, central nervous system malformation, synaptopathy, nervous system neoplasm, sensory ganglionopathy, radiculitis, wet beriberi, perceptual disorders, prepubertal anorexia nervosa, neurocutaneous syndrome, neurovascular disorder, Wallerian degeneration, nervous system injury, neurosarcoidosis, neuroendocrine disorder, tubulinopathy, atactic disorder, hereditary neurological disease, meningitis-retention syndrome, KIF1A related neurological disorder, neurological pain disorder, neurodevelopmental disorder, post 5-alpha-reductase inhibitors treatment syndrome, post-selective serotonin reuptake inhibitor sexual dysfunction

Subtypes (1): familial periodic paralysis

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

3 retrieved; paginated sample, class counts are floors:

2 conflicting classifications of pathogenicity, 1 uncertain significance

ClinVar	Variant (HGVS)	Gene	Classification	Review
5541	NM_005472.5(KCNE3):c.248G>A (p.Arg83His)	KCNE3	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
183157	NM_001199107.2(TBC1D24):c.1079G>T (p.Arg360Leu)	TBC1D24	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
1981804	NM_000702.4(ATP1A2):c.682G>A (p.Glu228Lys)	ATP1A2	Uncertain significance	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 13 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
TBC1D24	Orphanet:163727	Rolandic epilepsy-paroxysmal exercise-induced dystonia-writer’s cramp syndrome
TBC1D24	Orphanet:293181	Epilepsy of infancy with migrating focal seizures
TBC1D24	Orphanet:352582	Familial infantile myoclonic epilepsy
TBC1D24	Orphanet:352587	Focal epilepsy-intellectual disability-cerebro-cerebellar malformation
TBC1D24	Orphanet:352596	Progressive myoclonic epilepsy with dystonia
TBC1D24	Orphanet:79500	DOORS syndrome
TBC1D24	Orphanet:90635	Rare autosomal dominant non-syndromic sensorineural deafness type DFNA
TBC1D24	Orphanet:90636	Rare autosomal recessive non-syndromic sensorineural deafness type DFNB
KCNE3	Orphanet:130	Brugada syndrome
KCNE3	Orphanet:681	Hypokalemic periodic paralysis
ATP1A2	Orphanet:2131	Alternating hemiplegia of childhood
ATP1A2	Orphanet:442835	Non-specific early-onset epileptic encephalopathy
ATP1A2	Orphanet:569	Familial or sporadic hemiplegic migraine

Cohort genes → proteins

3 cohort genes, 3 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	3

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
TBC1D24	HGNC:29203	ENSG00000162065	Q9ULP9	TBC1 domain family member 24	clinvar
KCNE3	HGNC:6243	ENSG00000175538	Q9Y6H6	Potassium voltage-gated channel subfamily E member 3	clinvar
ATP1A2	HGNC:800	ENSG00000018625	P50993	Sodium/potassium-transporting ATPase subunit alpha-2	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
TBC1D24	TBC1 domain family member 24	May act as a GTPase-activating protein for Rab family protein(s).
KCNE3	Potassium voltage-gated channel subfamily E member 3	Ancillary protein that functions as a regulatory subunit of the voltage-gated potassium (Kv) channel complex composed of pore-forming and potassium-conducting alpha subunits and of regulatory beta subunits.
ATP1A2	Sodium/potassium-transporting ATPase subunit alpha-2	This is the catalytic component of the active enzyme, which catalyzes the hydrolysis of ATP coupled with the exchange of sodium and potassium ions across the plasma membrane.

Protein-family classification

Druggable: 1 · Difficult: 1 · Unknown: 1 · Druggable fraction: 0.33

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	37.2×	0.080
Transcription factor	1	2.8×	0.482
Other/Unknown	1	0.6×	0.914

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
TBC1D24	Other/Unknown	no		Rab-GAP-TBC_dom, TLDc_dom, Rab-GAP_TBC_sf
KCNE3	Ion channel	yes		K_chnl_KCNE, K_chnl_volt-dep_bsu_KCNE3
ATP1A2	Transcription factor	no		P_typ_ATPase, ATPase_P-typ_cation-transptr_N, P-type_ATPase_IIC

Expression context

Cohort genes with no expression data: 0.

3 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)	3
unknown	0

Top tissues across cohort

Tissue	Cohort genes
Brodmann (1909) area 23	1
middle temporal gyrus	1
parotid gland	1
leukocyte	1
monocyte	1
nasal cavity epithelium	1
lateral globus pallidus	1
superior vestibular nucleus	1
trigeminal ganglion	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
TBC1D24	227	ubiquitous	marker	parotid gland, Brodmann (1909) area 23, middle temporal gyrus
KCNE3	227	broad	marker	nasal cavity epithelium, monocyte, leukocyte
ATP1A2	262	broad	marker	lateral globus pallidus, trigeminal ganglion, superior vestibular nucleus

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ATP1A2	2,679
KCNE3	1,467
TBC1D24	1,016

Structural data

PDB: 1 · AlphaFold-only: 2 · No structure: 0

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
KCNE3	Q9Y6H6	4

AlphaFold-only cohort genes (top 30 by pLDDT)

Symbol	UniProt	pLDDT
ATP1A2	P50993	88.25
TBC1D24	Q9ULP9	84.46

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 17. Enrichment computed across 3 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
Cardiac conduction	2	72.5×	0.004	KCNE3, ATP1A2
Muscle contraction	2	51.4×	0.004	KCNE3, ATP1A2
Phase 3 - rapid repolarisation	1	380.7×	0.015	KCNE3
Phase 2 - plateau phase	1	253.8×	0.017	KCNE3
Rab regulation of trafficking	1	122.8×	0.028	TBC1D24
TBC/RABGAPs	1	86.5×	0.031	TBC1D24
Ion transport by P-type ATPases	1	69.2×	0.031	ATP1A2
Ion homeostasis	1	68.0×	0.031	ATP1A2
Potential therapeutics for SARS	1	38.1×	0.049	ATP1A2
Ion channel transport	1	32.0×	0.053	ATP1A2
SARS-CoV Infections	1	18.5×	0.082	ATP1A2
Membrane Trafficking	1	12.4×	0.109	TBC1D24
Vesicle-mediated transport	1	11.6×	0.109	TBC1D24
Viral Infection Pathways	1	10.3×	0.115	ATP1A2
Transport of small molecules	1	8.4×	0.123	ATP1A2
Infectious disease	1	8.3×	0.123	ATP1A2
Disease	1	4.4×	0.212	ATP1A2

GO biological processes 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.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
sodium ion transport	2	181.2×	0.003	KCNE3, ATP1A2
olfactory cortex development	1	5617.3×	0.004	ATP1A2
negative regulation of membrane repolarization during ventricular cardiac muscle cell action potential	1	5617.3×	0.004	KCNE3
regulation of glutamate uptake involved in transmission of nerve impulse	1	2808.7×	0.005	ATP1A2
negative regulation of calcium ion transmembrane transport	1	2808.7×	0.005	ATP1A2
negative regulation of striated muscle contraction	1	1872.4×	0.005	ATP1A2
negative regulation of heart contraction	1	1404.3×	0.005	ATP1A2
negative regulation of cellular response to oxidative stress	1	1404.3×	0.005	TBC1D24
amygdala development	1	936.2×	0.005	ATP1A2
negative regulation of delayed rectifier potassium channel activity	1	936.2×	0.005	KCNE3
response to glycoside	1	802.5×	0.005	ATP1A2
negative regulation of potassium ion export across plasma membrane	1	802.5×	0.005	KCNE3
regulation of striated muscle contraction	1	702.2×	0.005	ATP1A2
response to potassium ion	1	702.2×	0.005	ATP1A2
positive regulation of heart contraction	1	702.2×	0.005	ATP1A2
regulation of muscle contraction	1	561.7×	0.005	ATP1A2
intracellular chloride ion homeostasis	1	561.7×	0.005	KCNE3
membrane repolarization during action potential	1	561.7×	0.005	KCNE3
membrane repolarization during ventricular cardiac muscle cell action potential	1	561.7×	0.005	KCNE3
L-ascorbic acid metabolic process	1	510.7×	0.005	ATP1A2
locomotion	1	510.7×	0.005	ATP1A2
neurotransmitter uptake	1	468.1×	0.005	ATP1A2
neuronal action potential propagation	1	468.1×	0.005	ATP1A2
membrane depolarization during cardiac muscle cell action potential	1	468.1×	0.005	ATP1A2
cell communication by electrical coupling involved in cardiac conduction	1	468.1×	0.005	ATP1A2
regulation of respiratory gaseous exchange by nervous system process	1	432.1×	0.005	ATP1A2
negative regulation of cytosolic calcium ion concentration	1	432.1×	0.005	ATP1A2
relaxation of cardiac muscle	1	432.1×	0.005	ATP1A2
membrane repolarization	1	432.1×	0.005	ATP1A2
regulation of smooth muscle contraction	1	401.2×	0.005	ATP1A2

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 3 evidence-associated genes (33%) 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
ATP1A2	OMEPRAZOLE

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ATP1A2	5	4
TBC1D24	0	0
KCNE3	0	0

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
OMEPRAZOLE	4	ATP1A2
DIGOXIN	4	ATP1A2
DIGITOXIN	4	ATP1A2
LANSOPRAZOLE	4	ATP1A2
ROSTAFUROXIN	2	ATP1A2

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
ATP1A2	49	Binding:49

Pharmacogenomics

Cohort genes with a PharmGKB record: 3; 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)
OMEPRAZOLE	4	ATP1A2
DIGOXIN	4	ATP1A2
DIGITOXIN	4	ATP1A2
LANSOPRAZOLE	4	ATP1A2
ROSTAFUROXIN	2	ATP1A2

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	ATP1A2
B	Phased (≥1) drug, not yet approved	0
C	Druggable family + PDB, no drug	1	KCNE3
D	Druggable family + AlphaFold only, no drug	0
E	Difficult family or no structure, no drug	1	TBC1D24

Undrugged target profiles

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

Symbol	ChEMBL assays	Drugged partners (top 3)
TBC1D24	0	—
KCNE3	0	—

Clinical trials & evidence

Clinical trials

Clinical trials: 0.