Myotonia fluctuans

Summary

Myotonia fluctuans (MONDO:0020481) is a disease with 1 cohort gene and 7 clinical trials. Top therapeutic interventions include ruxolitinib and navtemadlin.

At a glance

• Prevalence: Unknown (Worldwide)
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 22
• Clinical trials: 7

Clinical features

Signs & symptoms

Clinical features (HPO)

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

HPO ID	Term	Frequency
HP:0003552	Muscle stiffness	Very frequent (80-99%)
HP:0100284	EMG: myotonic discharges	Very frequent (80-99%)
HP:0002491	Spasticity of facial muscles	Frequent (30-79%)
HP:0008967	Exercise-induced muscle stiffness	Frequent (30-79%)
HP:0012902	Myotonia of the lower limb	Frequent (30-79%)
HP:0012903	Myotonia of the upper limb	Frequent (30-79%)
HP:0000622	Blurred vision	Occasional (5-29%)
HP:0000651	Diplopia	Occasional (5-29%)
HP:0003326	Myalgia	Occasional (5-29%)
HP:0012378	Fatigue	Occasional (5-29%)
HP:0012899	Handgrip myotonia	Occasional (5-29%)
HP:0012900	Myotonia of the face	Occasional (5-29%)
HP:0012904	Cold-sensitive myotonia	Excluded (0%)
HP:0000486	Strabismus	Very rare (<1-4%)
HP:0001288	Gait disturbance	Very rare (<1-4%)
HP:0001319	Neonatal hypotonia	Very rare (<1-4%)
HP:0002104	Apnea	Very rare (<1-4%)
HP:0003701	Proximal muscle weakness	Very rare (<1-4%)
HP:0003740	Myotonia with warm-up phenomenon	Very rare (<1-4%)
HP:0010307	Stridor	Very rare (<1-4%)
HP:0025425	Laryngospasm	Very rare (<1-4%)
HP:0030842	Choking episodes	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	myotonia fluctuans
Mondo ID	MONDO:0020481
Orphanet	99734
ICD-11	1294270721
NCIT	C122789
SNOMED CT	715788001
UMLS	C0752355
MedGen	156269
GARD	0016904
Is cancer (heuristic)	no

Also known as: exercise-induced delayed-onset myotonia · Fluctuating myotonia · MF

Data availability: 2 ClinVar variants · 1 GenCC gene-disease record.

Disease family

Classification path: disease › human disease › disease by body system or component › syndromic disease › myotonic syndrome › potassium-aggravated myotonia › myotonia fluctuans

Related subtypes (2): myotonia permanens, acetazolamide-responsive myotonia

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

2 retrieved; paginated sample, class counts are floors:

2 pathogenic/likely pathogenic

ClinVar	Variant (HGVS)	Gene	Classification	Review
5901	NM_000334.4(SCN4A):c.2411C>T (p.Ser804Phe)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts
5908	NM_000334.4(SCN4A):c.3917G>C (p.Gly1306Ala)	GH-LCR	Pathogenic/Likely pathogenic	criteria provided, multiple submitters, no conflicts

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 24 · Orphanet: 7 · 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	Strong	Autosomal dominant	potassium-aggravated myotonia	24

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

Cohort genes → proteins

1 cohort genes, 1 distinct canonical proteins.

Evidence partition

Subset	Genes
multi_evidence	1

Cohort genes (full)

Symbol	HGNC	Ensembl	UniProt	Name	Evidence
SCN4A	HGNC:10591	ENSG00000007314	P35499	Sodium channel protein type 4 subunit alpha	gencc

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.

Protein-family classification

Druggable: 1 · 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	1	111.5×	0.009

Per-gene assignment

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

Expression context

Cohort genes with no expression data: 0.

Breadth distribution (Bgee present_calls)

Bucket	Genes
narrow (1-5 tissues)	0
moderate (6-20)	0
broad (>20)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
gastrocnemius	1
hindlimb stylopod muscle	1
skeletal muscle tissue of rectus abdominis	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

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
SCN4A	1,704

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
SCN4A	P35499	3

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 8. Enrichment computed across 1 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
Interaction between L1 and Ankyrins	1	368.4×	0.012	SCN4A
Phase 0 - rapid depolarisation	1	346.1×	0.012	SCN4A
L1CAM interactions	1	120.2×	0.018	SCN4A
Cardiac conduction	1	108.8×	0.018	SCN4A
Muscle contraction	1	77.2×	0.021	SCN4A
Axon guidance	1	45.1×	0.027	SCN4A
Nervous system development	1	42.9×	0.027	SCN4A
Developmental Biology	1	14.5×	0.069	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 1 annotated cohort genes). Counts and members are kept as ground-truth; sorted by enrichment.

GO term	Cohort genes	Fold	FDR	Sample cohort genes
regulation of skeletal muscle contraction by action potential	1	16852.0×	3e-04	SCN4A
cardiac muscle cell action potential involved in contraction	1	702.2×	0.004	SCN4A
sodium ion transport	1	271.8×	0.005	SCN4A
muscle contraction	1	208.1×	0.005	SCN4A
sodium ion transmembrane transport	1	203.0×	0.005	SCN4A

Therapeutics

Drug target analysis

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

Druggability breadth: 1 of 1 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

Top cohort targets by molecule count

Symbol	Molecules	Max phase
SCN4A	24	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
CARBAMAZEPINE	4	SCN4A
PHENYTOIN	4	SCN4A
LAMOTRIGINE	4	SCN4A
RILUZOLE	4	SCN4A
LIDOCAINE	4	SCN4A
IMIPRAMINE	4	SCN4A
SERTINDOLE	4	SCN4A
PIMOZIDE	4	SCN4A
NIFEDIPINE	4	SCN4A
DILTIAZEM	4	SCN4A
MIBEFRADIL	4	SCN4A
HALOPERIDOL	4	SCN4A
MEXILETINE	4	SCN4A
AMITRIPTYLINE	4	SCN4A
AMIODARONE	4	SCN4A
CHLORPROMAZINE	4	SCN4A
VIXOTRIGINE	3	SCN4A
ELECLAZINE	3	SCN4A
TETRODOTOXIN	3	SCN4A
TEDISAMIL	3	SCN4A
NITRENDIPINE	3	SCN4A
AJMALINE	3	SCN4A
PF-05089771	2	SCN4A
CIFENLINE	2	SCN4A

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 0.

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

Symbol	Assays	Type breakdown
SCN4A	95	Binding:69, Functional:18, ADMET:7, Toxicity:1

Pharmacogenomics

Cohort genes with a PharmGKB record: 1; with CPIC/DPWG dosing guidelines: 0.

No cohort gene has a CPIC/DPWG genotype-guided dosing guideline (PharmGKB).

Chemical tractability of cohort targets

24 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	SCN4A
LAMOTRIGINE	4	SCN4A
RILUZOLE	4	SCN4A
LIDOCAINE	4	SCN4A
IMIPRAMINE	4	SCN4A
SERTINDOLE	4	SCN4A
PIMOZIDE	4	SCN4A
NIFEDIPINE	4	SCN4A
DILTIAZEM	4	SCN4A
MIBEFRADIL	4	SCN4A
HALOPERIDOL	4	SCN4A
MEXILETINE	4	SCN4A
AMITRIPTYLINE	4	SCN4A
AMIODARONE	4	SCN4A
CHLORPROMAZINE	4	SCN4A
VIXOTRIGINE	3	SCN4A
ELECLAZINE	3	SCN4A
TETRODOTOXIN	3	SCN4A
TEDISAMIL	3	SCN4A
NITRENDIPINE	3	SCN4A
AJMALINE	3	SCN4A
PF-05089771	2	SCN4A
CIFENLINE	2	SCN4A

Druggability pyramid

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

Tier	Definition	Genes	Symbols
A	Approved (phase 4 drug)	1	SCN4A
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: 7.

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	2
Not specified	2
PHASE1/PHASE2	1
PHASE2	1
PHASE1	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT06479135	PHASE3	RECRUITING	Study of Navtemadlin add-on to Ruxolitinib in JAK Inhibitor-Naïve Patients With Myelofibrosis Who Have a Suboptimal Response to Ruxolitinib
NCT07317700	PHASE3	RECRUITING	A Clinical Trial of Flonoltinib Maleate for Intermediate or High-Risk Myelofibrosis
NCT04686682	PHASE1/PHASE2	RECRUITING	A First-in-Human, JAB-8263 in Adult Patients With Advanced Tumors
NCT07443306	PHASE2	RECRUITING	A Clinical Trial of Flonoltinib Maleate Tablets in the Treatment of JAK Inhibitor Refractory/Relapsed/Intolerant Patients With Medium to High Risk Myelofibrosis
NCT07612306	PHASE1	NOT_YET_RECRUITING	Material Balance Study of [14C] Flonoltinib Maleate
NCT07362225	Not specified	RECRUITING	MPN PROGRESSion Registry: Observational Study Tracking Symptoms, Treatments, and Disease Progression in People With Myeloproliferative Neoplasms (MPNs)
NCT02469974	Not specified	WITHDRAWN	Ruxolitinib in Combination With Autotransplant

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
RUXOLITINIB	4	4
NAVTEMADLIN	3	1
CHEMBL4637163	0	1