Exercise-induced malignant hyperthermia

Summary

Exercise-induced malignant hyperthermia (MONDO:0018752) is a disease with 1 cohort gene and 1 clinical trial. Top therapeutic interventions include dantrolene sodium.

At a glance

• Prevalence: Unknown (Worldwide) [Orphanet-validated]
• Cohort genes: 1
• ClinVar variants: 2
• Phenotypes (HPO): 41
• Clinical trials: 1

Clinical features

Signs & symptoms

Clinical features (HPO)

41 HPO clinical features (Orphanet curated; top 41 by frequency):

HPO ID	Term	Frequency
HP:0000707	Abnormality of the nervous system	Very frequent (80-99%)
HP:0002047	Malignant hyperthermia	Very frequent (80-99%)
HP:0002018	Nausea	Frequent (30-79%)
HP:0002315	Headache	Frequent (30-79%)
HP:0002321	Vertigo	Frequent (30-79%)
HP:0002789	Tachypnea	Frequent (30-79%)
HP:0011703	Sinus tachycardia	Frequent (30-79%)
HP:0012378	Fatigue	Frequent (30-79%)
HP:0030850	Abnormal pulse pressure	Frequent (30-79%)
HP:0001250	Seizure	Occasional (5-29%)
HP:0001251	Ataxia	Occasional (5-29%)
HP:0001254	Lethargy	Occasional (5-29%)
HP:0001289	Confusion	Occasional (5-29%)
HP:0001324	Muscle weakness	Occasional (5-29%)
HP:0001410	Decreased liver function	Occasional (5-29%)
HP:0001657	Prolonged QT interval	Occasional (5-29%)
HP:0001892	Abnormal bleeding	Occasional (5-29%)
HP:0002013	Vomiting	Occasional (5-29%)
HP:0002153	Hyperkalemia	Occasional (5-29%)
HP:0002615	Hypotension	Occasional (5-29%)
HP:0002901	Hypocalcemia	Occasional (5-29%)
HP:0002905	Hyperphosphatemia	Occasional (5-29%)
HP:0003128	Lactic acidosis	Occasional (5-29%)
HP:0003236	Elevated circulating creatine kinase concentration	Occasional (5-29%)
HP:0003256	Abnormality of the coagulation cascade	Occasional (5-29%)
HP:0003710	Exercise-induced muscle cramps	Occasional (5-29%)
HP:0005135	Abnormal T-wave	Occasional (5-29%)
HP:0012250	ST segment depression	Occasional (5-29%)
HP:0012417	Hypocapnia	Occasional (5-29%)
HP:0030830	Crackles	Occasional (5-29%)
HP:0031258	Delirium	Occasional (5-29%)
HP:0031284	Flushing	Occasional (5-29%)
HP:0100520	Oliguria	Occasional (5-29%)
HP:0000958	Dry skin	Very rare (<1-4%)
HP:0000970	Anhidrosis	Very rare (<1-4%)
HP:0001399	Hepatic failure	Very rare (<1-4%)
HP:0001873	Thrombocytopenia	Very rare (<1-4%)
HP:0001919	Acute kidney injury	Very rare (<1-4%)
HP:0002480	Hepatic encephalopathy	Very rare (<1-4%)
HP:0003201	Rhabdomyolysis	Very rare (<1-4%)
HP:0005521	Disseminated intravascular coagulation	Very rare (<1-4%)

Identifiers

Disease identifiers

Field	Value
Canonical name	exercise-induced malignant hyperthermia
Mondo ID	MONDO:0018752
Orphanet	466650
SNOMED CT	735907005
UMLS	C5700399
MedGen	1814609
GARD	0021936
Is cancer (heuristic)	no

Also known as: Exertional heat stroke

Data availability: 2 ClinVar variants.

Disease family

Classification path: disease › human disease › disease by body system or component › nervous system disorder › exercise-induced malignant hyperthermia

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, periodic paralysis, 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, 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

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:

1 pathogenic, 1 likely benign

ClinVar	Variant (HGVS)	Gene	Classification	Review
1683484	NM_004318.4(ASPH):c.322+12720A>C	ASPH	Pathogenic	no assertion criteria provided
1683486	NM_004318.4(ASPH):c.323-11619A>G	ASPH	Likely benign	criteria provided, single submitter

Genes & proteins

Mendelian disease overlap and somatic drivers

GenCC: 0 · Orphanet: 1 · OMIM-shared: 0 · Dual-evidence (GWAS+Mendelian): 0

Orphanet rare-disease linkage (cohort genes)

Gene	Orphanet ID	Rare disease
ASPH	Orphanet:412022	Facial dysmorphism-lens dislocation-anterior segment abnormalities-spontaneous filtering blebs syndrome

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
ASPH	HGNC:757	ENSG00000198363	Q12797	Aspartyl/asparaginyl beta-hydroxylase	clinvar

Cohort function summary

Lead sentence per gene, UniProt-curated.

Symbol	Protein name	Function (lead sentence)
ASPH	Aspartyl/asparaginyl beta-hydroxylase	Specifically hydroxylates an Asp or Asn residue in certain epidermal growth factor-like (EGF) domains of a number of proteins.

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
Enzyme (other)	1	12.0×	0.083

Per-gene assignment

Symbol	Family	Druggable?	EC	InterPro (top 3)
ASPH	Enzyme (other)	yes	1.14.11.16	Asp/Arg/Pro-Hydrxlase, Asp-B-hydro/Triadin_dom, TPR-like_helical_dom_sf

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)	1
unknown	0

Top tissues across cohort

Tissue	Cohort genes
calcaneal tendon	1
palpebral conjunctiva	1
stromal cell of endometrium	1

Per-gene tissue summary (top 30)

Symbol	Bgee breadth	FANTOM5 breadth	SCXA	Top tissues
ASPH	289	ubiquitous	marker	calcaneal tendon, stromal cell of endometrium, palpebral conjunctiva

Protein interactions among cohort

Intra-cohort edges: 0.

Hub genes (top 10 by interactor count)

Symbol	Interactor count
ASPH	1,866

Structural data

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

Cohort genes with PDB structures (top 30)

Symbol	UniProt	PDB entries
ASPH	Q12797	43

Function

Pathway analysis

Distinct Reactome pathways touched by cohort: 10. 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
Protein hydroxylation	1	543.8×	0.012	ASPH
Gamma carboxylation, hypusinylation, hydroxylation, and arylsulfatase activation	1	423.0×	0.012	ASPH
Ion homeostasis	1	203.9×	0.016	ASPH
Stimuli-sensing channels	1	135.9×	0.017	ASPH
Cardiac conduction	1	108.8×	0.017	ASPH
Ion channel transport	1	96.0×	0.017	ASPH
Muscle contraction	1	77.2×	0.019	ASPH
Transport of small molecules	1	25.1×	0.050	ASPH
Post-translational protein modification	1	19.2×	0.058	ASPH
Metabolism of proteins	1	12.4×	0.081	ASPH

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
obsolete regulation of inositol 1,4,5-trisphosphate-sensitive calcium-release channel activity	1	16852.0×	7e-04	ASPH
regulation of protein depolymerization	1	16852.0×	7e-04	ASPH
activation of store-operated calcium channel activity	1	3370.4×	0.002	ASPH
regulation of cell communication by electrical coupling	1	2407.4×	0.002	ASPH
positive regulation of calcium ion transport into cytosol	1	1203.7×	0.003	ASPH
detection of calcium ion	1	1123.5×	0.003	ASPH
limb morphogenesis	1	1053.2×	0.003	ASPH
response to ATP	1	991.3×	0.003	ASPH
positive regulation of proteolysis	1	802.5×	0.003	ASPH
regulation of release of sequestered calcium ion into cytosol by sarcoplasmic reticulum	1	674.1×	0.003	ASPH
regulation of cardiac muscle contraction by regulation of the release of sequestered calcium ion	1	674.1×	0.003	ASPH
positive regulation of intracellular protein transport	1	674.1×	0.003	ASPH
face morphogenesis	1	495.6×	0.004	ASPH
pattern specification process	1	468.1×	0.004	ASPH
calcium ion homeostasis	1	443.5×	0.004	ASPH
regulation of cytosolic calcium ion concentration	1	383.0×	0.004	ASPH
roof of mouth development	1	247.8×	0.006	ASPH
calcium ion transmembrane transport	1	210.7×	0.006	ASPH
muscle contraction	1	208.1×	0.006	ASPH
cellular response to calcium ion	1	200.6×	0.006	ASPH
regulation of protein stability	1	125.8×	0.009	ASPH
cell population proliferation	1	102.8×	0.011	ASPH
negative regulation of cell population proliferation	1	42.1×	0.025	ASPH
positive regulation of DNA-templated transcription	1	27.9×	0.036	ASPH

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
ASPH	VEMURAFENIB

Top cohort targets by molecule count

Symbol	Molecules	Max phase
ASPH	13	4

Drugs targeting cohort genes (top 30)

Molecule	Max phase	Targets in cohort
VEMURAFENIB	4	ASPH
ROXADUSTAT	4	ASPH
VENETOCLAX	4	ASPH
DAPRODUSTAT	4	ASPH
VADADUSTAT	4	ASPH
BELINOSTAT	4	ASPH
BLEOMYCIN	4	ASPH
MIDOSTAURIN	4	ASPH
ENARODUSTAT	3	ASPH
NAVITOCLAX	3	ASPH
DESIDUSTAT	3	ASPH
GOSSYPOL	3	ASPH
ABT 737	1	ASPH

Bioactivity and enzyme data

Enzyme cohort genes (≥1 EC): 1.

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

Symbol	Assays	Type breakdown
ASPH	15	Binding:15

Cohort enzymes (BRENDA EC)

Symbol	EC numbers	Names
ASPH	1.14.11.16	peptide-aspartate beta-dioxygenase

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

13 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)
VEMURAFENIB	4	ASPH
ROXADUSTAT	4	ASPH
VENETOCLAX	4	ASPH
DAPRODUSTAT	4	ASPH
VADADUSTAT	4	ASPH
BELINOSTAT	4	ASPH
BLEOMYCIN	4	ASPH
MIDOSTAURIN	4	ASPH
ENARODUSTAT	3	ASPH
NAVITOCLAX	3	ASPH
DESIDUSTAT	3	ASPH
GOSSYPOL	3	ASPH
ABT 737	1	ASPH

Druggability pyramid

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

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

Phase distribution (across all retrieved trials)

Phase	Trials
PHASE3	1

Top trials by phase / activity

NCT	Phase	Status	Title
NCT03600376	PHASE3	COMPLETED	Study to Assess the Efficacy and Safety of Ryanodex as Adjuvant Treatment in Subjects With EHS

Drugs tested across these trials (top 30)

Molecule	Max phase	Trials referencing
DANTROLENE SODIUM	4	1