Hypokalemic periodic paralysis

Summary

Hypokalemic periodic paralysis (MONDO:0008223) is a disease with 2 cohort genes and 5 clinical trials. Top therapeutic interventions include dichlorphenamide and bumetanide.

At a glance

• Prevalence: 1-9 / 100 000 (Europe) [Orphanet-validated]
• Cohort genes: 2
• ClinVar variants: 5
• Phenotypes (HPO): 22
• Clinical trials: 5

Clinical features

Epidemiology

Prevalence records

3 prevalence record(s), Orphanet:

Type	Class	Value	Geography	Validation
Point prevalence	1-9 / 100 000	1	Europe	Validated
Point prevalence	1-9 / 1 000 000	0.13	United Kingdom	Validated
Point prevalence	1-9 / 1 000 000	0.53	Netherlands	Validated

Signs & symptoms

Clinical features (HPO)

22 HPO clinical features (Orphanet curated; top 22 by frequency):

HPO ID	Term	Frequency
HP:0008153	Periodic hypokalemic paresis	Obligate (100%)
HP:0012726	Episodic hypokalemia	Obligate (100%)
HP:0003457	EMG abnormality	Very frequent (80-99%)
HP:0003470	Paralysis	Very frequent (80-99%)
HP:0003752	Episodic flaccid weakness	Very frequent (80-99%)
HP:0004303	Abnormal muscle fiber morphology	Very frequent (80-99%)
HP:0008180	Mildly elevated creatine kinase	Very frequent (80-99%)
HP:0012240	Increased intramyocellular lipid droplets	Very frequent (80-99%)
HP:0001315	Reduced tendon reflexes	Frequent (30-79%)
HP:0009020	Exercise-induced muscle fatigue	Frequent (30-79%)
HP:0011998	Postprandial hyperglycemia	Frequent (30-79%)
HP:0002747	Respiratory insufficiency due to muscle weakness	Occasional (5-29%)
HP:0003394	Muscle spasm	Occasional (5-29%)
HP:0003694	Late-onset proximal muscle weakness	Occasional (5-29%)
HP:0011675	Arrhythmia	Occasional (5-29%)
HP:0012531	Pain	Occasional (5-29%)
HP:0012548	Fatty replacement of skeletal muscle	Occasional (5-29%)
HP:0002486	Myotonia	Excluded (0%)
HP:0006670	Impaired myocardial contractility	Excluded (0%)
HP:0002203	Respiratory paralysis	Very rare (<1-4%)
HP:0008256	Adrenocortical adenoma	Very rare (<1-4%)
HP:0030196	Fatigable weakness of respiratory muscles	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	hypokalemic periodic paralysis
Mondo ID	MONDO:0008223
MeSH	D020514
Orphanet	681
DOID	DOID:14452
ICD-11	1494773635
NCIT	C84775
SNOMED CT	82732003
UMLS	C0238358
MedGen	116058
GARD	0006729
Is cancer (heuristic)	no

Also known as: familial periodic paralysis (& [hypokalaemic]) · HKPP · HOKPP · hypokalemic periodic paralysis · HypoPP · periodic paralysis I · Westphall disease

Data availability: 5 ClinVar variants · 2 GenCC gene-disease records.

Disease family

An umbrella term covering 2 Mondo subtypes.

Classification path: disease › human disease › disease by etiologic mechanism › disease of genetic or genomic mechanism › hereditary disease › inborn errors of metabolism › inborn metal metabolism disorder › familial periodic paralysis › hypokalemic periodic paralysis

Related subtypes (5): Andersen-Tawil syndrome, hyperkalemic periodic paralysis, normokalemic periodic paralysis, periodic paralysis with later-onset distal motor neuropathy, thyrotoxic periodic paralysis

Subtypes (2): hypokalemic periodic paralysis, type 2, hypokalemic periodic paralysis, type 1

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

5 retrieved; paginated sample, class counts are floors:

2 conflicting classifications of pathogenicity, 2 pathogenic/likely pathogenic, 1 benign/likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
849085	NM_000069.3(CACNA1S):c.1582C>T (p.Arg528Cys)	CACNA1S	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5916	NM_000334.4(SCN4A):c.2014C>A (p.Arg672Ser)	SCN4A	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
1804873	NM_000069.3(CACNA1S):c.4931T>A (p.Leu1644Ter)	CACNA1S	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
21035	NM_000069.3(CACNA1S):c.3256C>T (p.Arg1086Cys)	CACNA1S	Conflicting classifications of pathogenicity	criteria provided, conflicting classifications
254827	NM_000069.3(CACNA1S):c.3795+3G>A	CACNA1S	Benign/Likely benign	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 35 · Orphanet: 11 · 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
SCN4A	Definitive	Autosomal dominant	hyperkalemic periodic paralysis	24
CACNA1S	Strong	Autosomal dominant	hypokalemic periodic paralysis, type 1	11

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
SCN4A	Orphanet:681	Hypokalemic periodic paralysis
SCN4A	Orphanet:682	Hyperkalemic periodic paralysis
SCN4A	Orphanet:684	Paramyotonia congenita of Von Eulenburg
SCN4A	Orphanet:98913	Postsynaptic congenital myasthenic syndrome
SCN4A	Orphanet:99734	Myotonia fluctuans
SCN4A	Orphanet:99735	Myotonia permanens
SCN4A	Orphanet:99736	Acetazolamide-responsive myotonia
CACNA1S	Orphanet:397755	Periodic paralysis with transient compartment-like syndrome
CACNA1S	Orphanet:423	Malignant hyperthermia of anesthesia
CACNA1S	Orphanet:681	Hypokalemic periodic paralysis
CACNA1S	Orphanet:79102	Thyrotoxic periodic paralysis

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
SCN4A	HGNC:10591	ENSG00000007314	P35499	Sodium channel protein type 4 subunit alpha	gencc,clinvar
CACNA1S	HGNC:1397	ENSG00000081248	Q13698	Voltage-dependent L-type calcium channel subunit alpha-1S	gencc,clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
SCN4A	Sodium channel protein type 4 subunit alpha	Pore-forming subunit of Nav1.4, a voltage-gated sodium (Nav) channel that directly mediates the depolarizing phase of action potentials in excitable membranes.
CACNA1S	Voltage-dependent L-type calcium channel subunit alpha-1S	Pore-forming, alpha-1S subunit of the voltage-gated calcium channel that gives rise to L-type calcium currents in skeletal muscle.

Protein-family classification

Druggable: 2 · Difficult: 0 · Unknown: 0 · Druggable fraction: 1.0

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	111.5×	8e-05

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
SCN4A	Ion channel	yes		Na_channel_asu, Ion_trans_dom, Na_channel_a4su_mammal
CACNA1S	Ion channel	yes		VDCCAlpha1, VDCC_L_a1su, VDCC_L_a1ssu

Expression context

Cohort genes with no expression data: 0.

1 cohort gene 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
hindlimb stylopod muscle	2
gastrocnemius	1
skeletal muscle tissue of rectus abdominis	1
gluteal muscle	1
triceps brachii	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
SCN4A	153	tissue_specific	yes	hindlimb stylopod muscle, gastrocnemius, skeletal muscle tissue of rectus abdominis
CACNA1S	105	tissue_specific	marker	gluteal muscle, hindlimb stylopod muscle, triceps brachii

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
CACNA1S	1,818
SCN4A	1,704

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN4A	P35499	3
CACNA1S	Q13698	2

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. Enrichment computed across 2 evidence-associated genes (2 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 2 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

Pathway	Cohort genes	Fold	FDR	Sample cohort genes
Axon guidance	2	45.1×	0.003	SCN4A, CACNA1S
Nervous system development	2	42.9×	0.003	SCN4A, CACNA1S
Interaction between L1 and Ankyrins	1	184.2×	0.011	SCN4A
Phase 0 - rapid depolarisation	1	173.0×	0.011	SCN4A
NCAM signaling for neurite out-growth	1	135.9×	0.011	CACNA1S
NCAM1 interactions	1	124.1×	0.011	CACNA1S
Developmental Biology	2	14.5×	0.011	SCN4A, CACNA1S
L1CAM interactions	1	60.1×	0.020	SCN4A
Cardiac conduction	1	54.4×	0.020	SCN4A
Muscle contraction	1	38.6×	0.026	SCN4A

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
muscle contraction	2	208.1×	4e-04	SCN4A, CACNA1S
skeletal muscle adaptation	1	8426.0×	8e-04	CACNA1S
regulation of skeletal muscle contraction by action potential	1	8426.0×	8e-04	SCN4A
extraocular skeletal muscle development	1	1404.3×	0.003	CACNA1S
positive regulation of muscle contraction	1	1203.7×	0.003	CACNA1S
cellular response to caffeine	1	766.0×	0.004	CACNA1S
striated muscle contraction	1	421.3×	0.006	CACNA1S
cardiac muscle cell action potential involved in contraction	1	351.1×	0.006	SCN4A
myoblast fusion	1	300.9×	0.006	CACNA1S
skeletal muscle fiber development	1	271.8×	0.006	CACNA1S
calcium ion import across plasma membrane	1	271.8×	0.006	CACNA1S
neuromuscular junction development	1	263.3×	0.006	CACNA1S
endoplasmic reticulum organization	1	210.7×	0.007	CACNA1S
release of sequestered calcium ion into cytosol	1	172.0×	0.008	CACNA1S
sodium ion transport	1	135.9×	0.009	SCN4A
calcium ion transmembrane transport	1	105.3×	0.011	CACNA1S
sodium ion transmembrane transport	1	101.5×	0.011	SCN4A
calcium ion transport	1	90.6×	0.012	CACNA1S
skeletal system development	1	62.9×	0.016	CACNA1S

Therapeutics

Drugs indicated or in trials for this disease

No drug has an approved disease-direct ChEMBL indication for this disease.

2 drugs in clinical trials for this disease (phase 2–3, investigational): efficacy not established — a trial record, not an indication.

Drug	Highest phase
Dichlorphenamide	Phase 3
Bumetanide	Phase 2

Drug target analysis

Approved (phase 4): 2 · Phase ≥3: 2 · Phased (≥1): 2 · Undrugged: 0

Druggability breadth: 2 of 2 evidence-associated genes (100%) 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
SCN4A	CARBAMAZEPINE
CACNA1S	BEPRIDIL

Top cohort targets by molecule count

Symbol	Molecules	Max phase
CACNA1S	48	4
SCN4A	24	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CARBAMAZEPINE	4	SCN4A
PHENYTOIN	4	CACNA1S, SCN4A
LAMOTRIGINE	4	SCN4A
RILUZOLE	4	SCN4A
LIDOCAINE	4	SCN4A
IMIPRAMINE	4	CACNA1S, SCN4A
SERTINDOLE	4	CACNA1S, SCN4A
PIMOZIDE	4	CACNA1S, SCN4A
NIFEDIPINE	4	CACNA1S, SCN4A
DILTIAZEM	4	CACNA1S, SCN4A
MIBEFRADIL	4	CACNA1S, SCN4A
HALOPERIDOL	4	CACNA1S, SCN4A
MEXILETINE	4	CACNA1S, SCN4A
AMITRIPTYLINE	4	CACNA1S, SCN4A
AMIODARONE	4	CACNA1S, SCN4A
CHLORPROMAZINE	4	CACNA1S, SCN4A
BEPRIDIL	4	CACNA1S
HALOFANTRINE	4	CACNA1S
DROPERIDOL	4	CACNA1S
SAQUINAVIR	4	CACNA1S
DULOXETINE	4	CACNA1S
DIAZEPAM	4	CACNA1S
QUINIDINE	4	CACNA1S
LAMIVUDINE	4	CACNA1S
TERFENADINE	4	CACNA1S
CISAPRIDE	4	CACNA1S
SOLIFENACIN	4	CACNA1S
NILOTINIB	4	CACNA1S
ASTEMIZOLE	4	CACNA1S
TERODILINE	4	CACNA1S

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
CACNA1S	228	Binding:142, Functional:79, Toxicity:5, ADMET:2
SCN4A	95	Binding:69, Functional:18, ADMET:7, Toxicity:1

Cohort genes with high screening signal

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

Symbol	ChEMBL assays
CACNA1S	228

Pharmacogenomics

Cohort genes with a PharmGKB record: 2; with CPIC/DPWG dosing guidelines: 1.

Cohort genes with a CPIC/DPWG dosing guideline

Symbol	CPIC guidelines
CACNA1S	1

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)
CARBAMAZEPINE	4	SCN4A
PHENYTOIN	4	CACNA1S, SCN4A
LAMOTRIGINE	4	SCN4A
RILUZOLE	4	SCN4A
LIDOCAINE	4	SCN4A
IMIPRAMINE	4	CACNA1S, SCN4A
SERTINDOLE	4	CACNA1S, SCN4A
PIMOZIDE	4	CACNA1S, SCN4A
NIFEDIPINE	4	CACNA1S, SCN4A
DILTIAZEM	4	CACNA1S, SCN4A
MIBEFRADIL	4	CACNA1S, SCN4A
HALOPERIDOL	4	CACNA1S, SCN4A
MEXILETINE	4	CACNA1S, SCN4A
AMITRIPTYLINE	4	CACNA1S, SCN4A
AMIODARONE	4	CACNA1S, SCN4A
CHLORPROMAZINE	4	CACNA1S, SCN4A
BEPRIDIL	4	CACNA1S
HALOFANTRINE	4	CACNA1S
DROPERIDOL	4	CACNA1S
SAQUINAVIR	4	CACNA1S
DULOXETINE	4	CACNA1S
DIAZEPAM	4	CACNA1S
QUINIDINE	4	CACNA1S
LAMIVUDINE	4	CACNA1S
TERFENADINE	4	CACNA1S
CISAPRIDE	4	CACNA1S
SOLIFENACIN	4	CACNA1S
NILOTINIB	4	CACNA1S
ASTEMIZOLE	4	CACNA1S
TERODILINE	4	CACNA1S

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	2	SCN4A, CACNA1S
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	0

Undrugged target profiles

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

Clinical trials & evidence

Clinical trials

Clinical trials: 5.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	2
Not specified	2
PHASE2	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT00004802	PHASE3	COMPLETED	Phase III Randomized, Double-Blind, Placebo-Controlled Study of Dichlorphenamide for Periodic Paralyses and Associated Sodium Channel Disorders
NCT00494507	PHASE3	COMPLETED	Hyper- and Hypokalemic Periodic Paralysis Study
NCT02582476	PHASE2	TERMINATED	Bumetanide in Hypokalaemic Periodic Paralysis
NCT06917430	Not specified	NOT_YET_RECRUITING	Muscle MRI Outlining of Neuromuscular Diseases Using Artificial Intelligence
NCT07194174	Not specified	RECRUITING	Effect of Physical Training in Individuals With Hypokalemic and Hyperkalemic Periodic Paralysis

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DICHLORPHENAMIDE	4	2
BUMETANIDE	4	1