Malignant hyperthermia of anesthesia

Genetic MONDO:0018493 Pathograph 17 Muscular Channelopathy Hereditary Neuromuscular Disease

Malignant hyperthermia of anesthesia is an inherited pharmacogenetic skeletal muscle channelopathy in which susceptible individuals develop an acute hypermetabolic crisis after exposure to volatile anesthetic gases or succinylcholine. The central mechanism is dysregulated sarcoplasmic-reticulum calcium release during skeletal-muscle excitation-contraction coupling, which drives sustained contraction, carbon dioxide production, metabolic acidosis, hyperkalemia, rhabdomyolysis, fever, and potentially fatal cardiorespiratory collapse without prompt trigger withdrawal and dantrolene treatment.

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1
Mappings
0
Definitions
1
Inheritance
2
Pathophysiology
0
Histopathology
8
Phenotypes
17
Pathograph
3
Genes
2
Treatments
0
Subtypes
0
Differentials
0
Datasets
0
Trials
0
Models
1
References
1
Deep Research
🏷

Classifications

Channelopathy
skeletal muscle channelopathy
🔗

Mappings

MONDO
MONDO:0018493 malignant hyperthermia of anesthesia
skos:exactMatch MONDO
Primary MONDO disease identifier for this entry.
👪

Inheritance

1
Autosomal dominant HP:0000006
Human malignant hyperthermia susceptibility is usually autosomal dominant, although penetrance is incomplete and expression depends on exposure to triggering agents.
Autosomal dominant inheritance
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"In humans the syndrome is inherited in an autosomal dominant pattern, while in pigs it is autosomal recessive."
Supports autosomal dominant inheritance for the human susceptibility syndrome.
⚙

Pathophysiology

2
Trigger-dependent RyR1 calcium dysregulation
Triggering anesthetics or succinylcholine expose a latent defect in skeletal-muscle excitation-contraction coupling. In most genetically resolved cases this involves RYR1, with CACNA1S contributing a smaller fraction and STAC3 relevant mainly in biallelic syndromic myopathy. The affected channel complex permits uncontrolled myoplasmic calcium rise.
skeletal muscle cell link
RYR1 link CACNA1S link STAC3 link
release of sequestered calcium ion into cytosol by sarcoplasmic reticulum link ↑ INCREASED regulation of skeletal muscle contraction by calcium ion signaling link ↕ DYSREGULATED calcium ion transport link ↕ DYSREGULATED calcium ion homeostasis link ↕ DYSREGULATED
calcium channel activity link ↕ DYSREGULATED
sarcoplasmic reticulum link
skeletal muscle tissue link
Downstream
Hypermetabolic skeletal muscle crisis Uncontrolled calcium-dependent muscle activation drives sustained contraction, energy consumption, carbon dioxide production, heat production, and muscle breakdown.
Show evidence (2 references)
PMID:26238698 SUPPORT Human Clinical
"Uncontrolled rise of myoplasmic calcium, which activates biochemical processes related to muscle activation leads to the pathophysiologic changes. In most cases, the syndrome is caused by a defect in the ryanodine receptor."
Links uncontrolled myoplasmic calcium rise and ryanodine receptor defects to the core pathophysiologic mechanism.
PMID:32898259 SUPPORT Human Clinical
"Malignant hyperthermia susceptibility is a heritable trait, primarily associated with variants in either the type 1 ryanodine receptor (RYR1) intracellular calcium channel or the alpha 1S subunit (CACNA1S) of the voltage-dependent L-type Ca2+ channel."
Supports the principal RYR1/CACNA1S channel-complex genes included in this pathophysiology node.
Hypermetabolic skeletal muscle crisis
The downstream acute crisis is a skeletal-muscle hypermetabolic state with fever, tachycardia, increased carbon dioxide production, acidosis, hyperkalemia, rigidity, and rhabdomyolysis.
skeletal muscle cell link
skeletal muscle contraction link ↑ INCREASED regulation of skeletal muscle contraction by calcium ion signaling link ↕ DYSREGULATED calcium ion homeostasis link ↕ DYSREGULATED
skeletal muscle tissue link
Downstream
Malignant hyperthermia crisis The hypermetabolic skeletal-muscle state is the acute MH crisis.
Fever Heat production during the hypermetabolic crisis causes hyperthermia.
Tachycardia The systemic hypermetabolic stress response includes tachycardia.
Tachypnea Increased carbon dioxide production drives ventilatory signs including tachypnea.
Muscle rigidity Sustained calcium-driven skeletal-muscle contraction produces rigidity.
Rhabdomyolysis Sustained skeletal-muscle activation and injury produce rhabdomyolysis.
Hyperkalemia Muscle injury and crisis physiology produce hyperkalemia.
Metabolic acidosis Increased skeletal-muscle metabolism and carbon dioxide production contribute to acidosis.
End-tidal carbon dioxide Increased skeletal-muscle metabolism raises carbon dioxide production and end-tidal carbon dioxide.
Blood potassium Hyperkalemia is captured as increased blood potassium during the crisis.
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response."
Defines the hypermetabolic clinical state downstream of uncontrolled skeletal-muscle calcium release.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Malignant hyperthermia of anesthesia Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

8
Cardiovascular 1
Tachycardia Tachycardia (HP:0001649)
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response."
Tachycardia is included among the classic signs of MH.
Metabolism 4
Malignant hyperthermia crisis Malignant hyperthermia (HP:0002047)
Show evidence (1 reference)
PMID:37373564 SUPPORT Human Clinical
"Malignant hyperthermia is a rare but life-threatening pharmacogenetic disorder triggered by exposure to specific anesthetic agents."
Supports the defining acute pharmacogenetic crisis phenotype.
Fever Fever (HP:0001945)
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response."
Hyperthermia is listed as a classic sign of the acute MH response.
Hyperkalemia Hyperkalemia (HP:0002153)
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response."
Hyperkalemia is listed as a classic laboratory feature of MH.
Metabolic acidosis Metabolic acidosis (HP:0001942)
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response."
Acidosis is listed among the classic signs of the hypermetabolic MH response; the HPO term captures the metabolic component described in clinical summaries.
Musculoskeletal 2
Muscle rigidity Rigidity (HP:0002063)
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response."
Muscle rigidity is one of the classic signs produced by the calcium-driven hypermetabolic response.
Rhabdomyolysis Rhabdomyolysis (HP:0003201)
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response."
Rhabdomyolysis is listed as a classic manifestation of the acute MH crisis.
Respiratory 1
Tachypnea Tachypnea (HP:0002789)
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response."
Tachypnea is directly listed among the classic signs of malignant hyperthermia.
🧬

Genetic Associations

3
RYR1 susceptibility variants (Causative)
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"Over 400 variants have been identified in the RYR1 gene located on chromosome 19q13.1, and at least 34 are causal for MH."
Supports RYR1 as the major causal susceptibility gene.
CACNA1S susceptibility variants (Causative)
Show evidence (1 reference)
PMID:32898259 SUPPORT Human Clinical
"Malignant hyperthermia susceptibility is a heritable trait, primarily associated with variants in either the type 1 ryanodine receptor (RYR1) intracellular calcium channel or the alpha 1S subunit (CACNA1S) of the voltage-dependent L-type Ca2+ channel."
Supports CACNA1S as an established susceptibility gene, while the wording preserves its lesser role relative to RYR1.
STAC3-associated syndromic susceptibility (Disease-associated)
Show evidence (1 reference)
PMID:32898259 PARTIAL Human Clinical
"Another gene associated with malignant hyperthermia reactions is STAC3, although all the reported occurrences involve individuals with biallelic variants who have an apparent myopathy"
Supports a qualified STAC3 association while distinguishing syndromic biallelic myopathy-associated reactions from isolated MH susceptibility.
💊

Treatments

2
Dantrolene
Action: pharmacotherapy MAXO:0000058
Agent: dantrolene ↗
Dantrolene is the specific emergency pharmacotherapy for malignant hyperthermia and should be administered rapidly once MH is diagnosed or strongly suspected.
Mechanism Target:
INHIBITS Trigger-dependent RyR1 calcium dysregulation — Dantrolene antagonizes the calcium-release crisis mechanism and is the specific emergency pharmacotherapy for malignant hyperthermia.
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"Dantrolene sodium is a specific antagonist and should be available wherever general anesthesia is administered."
The review supports dantrolene as the specific antagonist for the MH mechanism.
Target Phenotypes: Malignant hyperthermia ↗
Show evidence (2 references)
PMID:26238698 SUPPORT Human Clinical
"Dantrolene sodium is a specific antagonist and should be available wherever general anesthesia is administered."
Establishes dantrolene as the specific MH antagonist and perioperative emergency drug.
PMID:36874927 SUPPORT Human Clinical
"Dantrolene should be given as rapidly as possible once MH has been diagnosed. Beginning treatment at a more normal body temperature can prevent critical elevations associated with a worse prognosis."
Retrospective clinical data support rapid dantrolene administration as a mortality-reducing intervention.
Trigger discontinuation and supportive crisis care
Action: supportive care MAXO:0000950
Crisis management includes immediate cessation of triggering agents, summoning expert support, hyperventilation and cooling as indicated, and correction of acidosis, hyperkalemia, arrhythmias, and renal complications.
Mechanism Target:
INHIBITS Trigger-dependent RyR1 calcium dysregulation — Removing volatile anesthetic or succinylcholine triggers stops further exposure of the susceptible calcium-release channel complex to the provoking stimulus.
Show evidence (1 reference)
PMID:35414440 SUPPORT Human Clinical
"As soon as the onset of MH is suspected, immediate cessation of exposure to stimuli, call for professional support, and access to dantrolene are the highest priorities."
The review supports immediate trigger cessation as a top-priority mechanism-directed action.
Target Phenotypes: Malignant hyperthermia ↗
Show evidence (1 reference)
PMID:35414440 SUPPORT Human Clinical
"As soon as the onset of MH is suspected, immediate cessation of exposure to stimuli, call for professional support, and access to dantrolene are the highest priorities."
Supports immediate trigger discontinuation and coordinated supportive emergency care.
🌍

Environmental Factors

1
Triggering anesthetic exposure
Volatile anesthetic gases and succinylcholine are the classic pharmacologic triggers; heat and exertion can rarely provoke related events in susceptible individuals.
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal muscle that presents as a hypermetabolic response to potent volatile anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane and the depolarizing muscle relaxant succinylcholine, and rarely, in humans, to..."
Defines the key anesthetic triggers and rarer non-anesthetic stressors.
🔬

Biochemical Markers

2
End-tidal carbon dioxide (INCREASED)
Context: Rising end-tidal carbon dioxide despite increased ventilation is an early diagnostic clue to the hypermetabolic skeletal-muscle crisis.
Pathograph Readouts
Readout Of Hypermetabolic skeletal muscle crisis Positive Diagnostic
Increased end-tidal carbon dioxide reports excess skeletal-muscle carbon dioxide production.
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"An increase in end-tidal carbon dioxide despite increased minute ventilation provides an early diagnostic clue."
This directly supports increased end-tidal carbon dioxide as an early diagnostic readout.
Show evidence (2 references)
PMID:26238698 SUPPORT Human Clinical
"An increase in end-tidal carbon dioxide despite increased minute ventilation provides an early diagnostic clue."
The review identifies increased end-tidal carbon dioxide as an early diagnostic clue.
PMID:35414440 SUPPORT Human Clinical
"characterized by rigidity of the masseter muscle, a high level of end-tidal carbon dioxide, and a sharp and persistent increase in body temperature."
Human review supports high end-tidal carbon dioxide during the preclinical/early MH stage.
Blood potassium (INCREASED)
Context: Increased circulating potassium is the biochemical correlate of hyperkalemia during severe malignant hyperthermia crises.
Pathograph Readouts
Readout Of Hypermetabolic skeletal muscle crisis Positive Diagnostic
Hyperkalemia reports systemic electrolyte disturbance during the MH crisis.
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response."
The review lists hyperkalemia among classic signs related to the hypermetabolic response.
Show evidence (1 reference)
PMID:26238698 SUPPORT Human Clinical
"The classic signs of MH include hyperthermia, tachycardia, tachypnea, increased carbon dioxide production, increased oxygen consumption, acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a hypermetabolic response."
Hyperkalemia in the classic-sign list supports increased blood potassium.
{ }

Source YAML

click to show 
name: Malignant hyperthermia of anesthesia
creation_date: '2026-05-09T12:44:09Z'
updated_date: '2026-05-20T17:40:22Z'
description: >-
  Malignant hyperthermia of anesthesia is an inherited pharmacogenetic skeletal
  muscle channelopathy in which susceptible individuals develop an acute
  hypermetabolic crisis after exposure to volatile anesthetic gases or
  succinylcholine. The central mechanism is dysregulated sarcoplasmic-reticulum
  calcium release during skeletal-muscle excitation-contraction coupling, which
  drives sustained contraction, carbon dioxide production, metabolic acidosis,
  hyperkalemia, rhabdomyolysis, fever, and potentially fatal cardiorespiratory
  collapse without prompt trigger withdrawal and dantrolene treatment.
synonyms:
- malignant hyperthermia
- malignant hyperpyrexia
- malignant hyperthermia syndrome
- malignant hyperthermia susceptibility
category: Genetic
references:
- reference: PMID:20301325
  title: Nonsyndromic Malignant Hyperthermia Susceptibility
  tags:
  - GeneReviews
disease_term:
  preferred_term: malignant hyperthermia of anesthesia
  term:
    id: MONDO:0018493
    label: malignant hyperthermia of anesthesia
mappings:
  mondo_mappings:
  - term:
      id: MONDO:0018493
      label: malignant hyperthermia of anesthesia
    mapping_predicate: skos:exactMatch
    mapping_source: MONDO
    mapping_justification: Primary MONDO disease identifier for this entry.
parents:
- Muscular Channelopathy
- Hereditary Neuromuscular Disease
classifications:
  channelopathy_category:
    classification_value: skeletal muscle channelopathy
prevalence:
- population: Genetic susceptibility
  percentage: as great as one in 400 individuals
  notes: >-
    Anesthetic reaction incidence is much lower than genetic susceptibility
    prevalence and ranges widely across anesthetic-exposure studies.
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The incidence of MH reactions ranges from 1:10,000 to 1: 250,000
      anesthetics. However, the prevalence of the genetic abnormalities may be
      as great as one in 400 individuals.
    explanation: >-
      Provides both the event incidence during anesthesia and the estimated
      upper prevalence of underlying genetic susceptibility.
inheritance:
- name: Autosomal dominant
  inheritance_term:
    preferred_term: Autosomal dominant inheritance
    term:
      id: HP:0000006
      label: Autosomal dominant inheritance
  description: >-
    Human malignant hyperthermia susceptibility is usually autosomal dominant,
    although penetrance is incomplete and expression depends on exposure to
    triggering agents.
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In humans the syndrome is inherited in an autosomal dominant pattern,
      while in pigs it is autosomal recessive.
    explanation: >-
      Supports autosomal dominant inheritance for the human susceptibility
      syndrome.
pathophysiology:
- name: Trigger-dependent RyR1 calcium dysregulation
  description: >-
    Triggering anesthetics or succinylcholine expose a latent defect in
    skeletal-muscle excitation-contraction coupling. In most genetically
    resolved cases this involves RYR1, with CACNA1S contributing a smaller
    fraction and STAC3 relevant mainly in biallelic syndromic myopathy. The
    affected channel complex permits uncontrolled myoplasmic calcium rise.
  genes:
  - preferred_term: RYR1
    term:
      id: hgnc:10483
      label: RYR1
  - preferred_term: CACNA1S
    term:
      id: hgnc:1397
      label: CACNA1S
  - preferred_term: STAC3
    term:
      id: hgnc:28423
      label: STAC3
  cell_types:
  - preferred_term: skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    term:
      id: GO:0014808
      label: release of sequestered calcium ion into cytosol by sarcoplasmic reticulum
    modifier: INCREASED
  - preferred_term: regulation of skeletal muscle contraction by calcium ion signaling
    term:
      id: GO:0014722
      label: regulation of skeletal muscle contraction by calcium ion signaling
    modifier: DYSREGULATED
  - preferred_term: calcium ion transport
    term:
      id: GO:0006816
      label: calcium ion transport
    modifier: DYSREGULATED
  - preferred_term: calcium ion homeostasis
    term:
      id: GO:0055074
      label: calcium ion homeostasis
    modifier: DYSREGULATED
  molecular_functions:
  - preferred_term: calcium channel activity
    term:
      id: GO:0005262
      label: calcium channel activity
    modifier: DYSREGULATED
  cellular_components:
  - preferred_term: sarcoplasmic reticulum
    term:
      id: GO:0016529
      label: sarcoplasmic reticulum
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Uncontrolled rise of myoplasmic calcium, which activates biochemical
      processes related to muscle activation leads to the pathophysiologic
      changes. In most cases, the syndrome is caused by a defect in the
      ryanodine receptor.
    explanation: >-
      Links uncontrolled myoplasmic calcium rise and ryanodine receptor defects
      to the core pathophysiologic mechanism.
  - reference: PMID:32898259
    reference_title: Genomic Screening for Malignant Hyperthermia Susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Malignant hyperthermia susceptibility is a heritable trait, primarily
      associated with variants in either the type 1 ryanodine receptor (RYR1)
      intracellular calcium channel or the alpha 1S subunit (CACNA1S) of the
      voltage-dependent L-type Ca2+ channel.
    explanation: >-
      Supports the principal RYR1/CACNA1S channel-complex genes included in
      this pathophysiology node.
  downstream:
  - target: Hypermetabolic skeletal muscle crisis
    causal_link_type: DIRECT
    description: >-
      Uncontrolled calcium-dependent muscle activation drives sustained
      contraction, energy consumption, carbon dioxide production, heat
      production, and muscle breakdown.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Uncontrolled rise of myoplasmic calcium, which activates biochemical
        processes related to muscle activation leads to the pathophysiologic
        changes.
      explanation: >-
        The review directly links uncontrolled myoplasmic calcium rise to the
        biochemical muscle-activation processes that produce the MH crisis.
- name: Hypermetabolic skeletal muscle crisis
  description: >-
    The downstream acute crisis is a skeletal-muscle hypermetabolic state with
    fever, tachycardia, increased carbon dioxide production, acidosis,
    hyperkalemia, rigidity, and rhabdomyolysis.
  cell_types:
  - preferred_term: skeletal muscle cell
    term:
      id: CL:0000188
      label: cell of skeletal muscle
  biological_processes:
  - preferred_term: skeletal muscle contraction
    term:
      id: GO:0003009
      label: skeletal muscle contraction
    modifier: INCREASED
  - preferred_term: regulation of skeletal muscle contraction by calcium ion signaling
    term:
      id: GO:0014722
      label: regulation of skeletal muscle contraction by calcium ion signaling
    modifier: DYSREGULATED
  - preferred_term: calcium ion homeostasis
    term:
      id: GO:0055074
      label: calcium ion homeostasis
    modifier: DYSREGULATED
  chemical_entities:
  - preferred_term: carbon dioxide
    term:
      id: CHEBI:16526
      label: carbon dioxide
    modifier: INCREASED
  - preferred_term: potassium
    term:
      id: CHEBI:29103
      label: potassium(1+)
    modifier: INCREASED
  locations:
  - preferred_term: skeletal muscle tissue
    term:
      id: UBERON:0001134
      label: skeletal muscle tissue
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The classic signs of MH include hyperthermia, tachycardia, tachypnea,
      increased carbon dioxide production, increased oxygen consumption,
      acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related
      to a hypermetabolic response.
    explanation: >-
      Defines the hypermetabolic clinical state downstream of uncontrolled
      skeletal-muscle calcium release.
  downstream:
  - target: Malignant hyperthermia crisis
    causal_link_type: DIRECT
    description: The hypermetabolic skeletal-muscle state is the acute MH crisis.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal
        muscle that presents as a hypermetabolic response to potent volatile
        anesthetic gases
      explanation: This directly defines MH as a skeletal-muscle hypermetabolic response.
  - target: Fever
    causal_link_type: DIRECT
    description: Heat production during the hypermetabolic crisis causes hyperthermia.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The classic signs of MH include hyperthermia, tachycardia, tachypnea,
        increased carbon dioxide production, increased oxygen consumption,
        acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all
        related to a hypermetabolic response.
      explanation: Hyperthermia is listed as a classic sign related to the hypermetabolic response.
  - target: Tachycardia
    causal_link_type: DIRECT
    description: The systemic hypermetabolic stress response includes tachycardia.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The classic signs of MH include hyperthermia, tachycardia, tachypnea,
        increased carbon dioxide production, increased oxygen consumption,
        acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all
        related to a hypermetabolic response.
      explanation: Tachycardia is listed as a classic sign related to the hypermetabolic response.
  - target: Tachypnea
    causal_link_type: DIRECT
    description: Increased carbon dioxide production drives ventilatory signs including tachypnea.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The classic signs of MH include hyperthermia, tachycardia, tachypnea,
        increased carbon dioxide production, increased oxygen consumption,
        acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all
        related to a hypermetabolic response.
      explanation: Tachypnea and increased carbon dioxide production are listed among signs of the hypermetabolic response.
  - target: Muscle rigidity
    causal_link_type: DIRECT
    description: Sustained calcium-driven skeletal-muscle contraction produces rigidity.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The classic signs of MH include hyperthermia, tachycardia, tachypnea,
        increased carbon dioxide production, increased oxygen consumption,
        acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all
        related to a hypermetabolic response.
      explanation: Muscle rigidity is listed as a classic sign related to the hypermetabolic response.
  - target: Rhabdomyolysis
    causal_link_type: DIRECT
    description: Sustained skeletal-muscle activation and injury produce rhabdomyolysis.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The classic signs of MH include hyperthermia, tachycardia, tachypnea,
        increased carbon dioxide production, increased oxygen consumption,
        acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all
        related to a hypermetabolic response.
      explanation: Rhabdomyolysis is listed as a classic sign related to the hypermetabolic response.
  - target: Hyperkalemia
    causal_link_type: DIRECT
    description: Muscle injury and crisis physiology produce hyperkalemia.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The classic signs of MH include hyperthermia, tachycardia, tachypnea,
        increased carbon dioxide production, increased oxygen consumption,
        acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all
        related to a hypermetabolic response.
      explanation: Hyperkalemia is listed as a classic sign related to the hypermetabolic response.
  - target: Metabolic acidosis
    causal_link_type: DIRECT
    description: Increased skeletal-muscle metabolism and carbon dioxide production contribute to acidosis.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The classic signs of MH include hyperthermia, tachycardia, tachypnea,
        increased carbon dioxide production, increased oxygen consumption,
        acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all
        related to a hypermetabolic response.
      explanation: Acidosis is listed as a classic sign related to the hypermetabolic response.
  - target: End-tidal carbon dioxide
    causal_link_type: DIRECT
    description: Increased skeletal-muscle metabolism raises carbon dioxide production and end-tidal carbon dioxide.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        An increase in end-tidal carbon dioxide despite increased minute
        ventilation provides an early diagnostic clue.
      explanation: The review supports increased end-tidal carbon dioxide as an early readout of the hypermetabolic crisis.
  - target: Blood potassium
    causal_link_type: DIRECT
    description: Hyperkalemia is captured as increased blood potassium during the crisis.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The classic signs of MH include hyperthermia, tachycardia, tachypnea,
        increased carbon dioxide production, increased oxygen consumption,
        acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all
        related to a hypermetabolic response.
      explanation: Hyperkalemia in the classic-sign list supports blood potassium as an increased biochemical readout.
phenotypes:
- name: Malignant hyperthermia crisis
  description: >-
    Acute anesthesia-associated hypermetabolic crisis with rapidly rising body
    temperature and systemic instability.
  phenotype_term:
    preferred_term: Malignant hyperthermia
    term:
      id: HP:0002047
      label: Malignant hyperthermia
  evidence:
  - reference: PMID:37373564
    reference_title: "Real Evidence and Misconceptions about Malignant Hyperthermia in Children: A Narrative Review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Malignant hyperthermia is a rare but life-threatening pharmacogenetic
      disorder triggered by exposure to specific anesthetic agents.
    explanation: >-
      Supports the defining acute pharmacogenetic crisis phenotype.
- name: Fever
  description: >-
    Body temperature rises during the hypermetabolic crisis and may become
    life-threatening if treatment is delayed.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The classic signs of MH include hyperthermia, tachycardia, tachypnea,
      increased carbon dioxide production, increased oxygen consumption,
      acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related
      to a hypermetabolic response.
    explanation: >-
      Hyperthermia is listed as a classic sign of the acute MH response.
- name: Tachycardia
  description: >-
    Rapid heart rate is part of the systemic response to increased skeletal
    muscle metabolism and sympathetic stress during the crisis.
  phenotype_term:
    preferred_term: Tachycardia
    term:
      id: HP:0001649
      label: Tachycardia
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The classic signs of MH include hyperthermia, tachycardia, tachypnea,
      increased carbon dioxide production, increased oxygen consumption,
      acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related
      to a hypermetabolic response.
    explanation: >-
      Tachycardia is included among the classic signs of MH.
- name: Tachypnea
  description: >-
    Rapid breathing is part of the acute hypermetabolic response during malignant
    hyperthermia crises.
  phenotype_term:
    preferred_term: Tachypnea
    term:
      id: HP:0002789
      label: Tachypnea
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The classic signs of MH include hyperthermia, tachycardia, tachypnea,
      increased carbon dioxide production, increased oxygen consumption, acidosis,
      hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related to a
      hypermetabolic response.
    explanation: >-
      Tachypnea is directly listed among the classic signs of malignant
      hyperthermia.
- name: Muscle rigidity
  description: >-
    Sustained skeletal-muscle contraction produces rigidity, including
    presentations with masseter spasm.
  phenotype_term:
    preferred_term: Muscle rigidity
    term:
      id: HP:0002063
      label: Rigidity
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The classic signs of MH include hyperthermia, tachycardia, tachypnea,
      increased carbon dioxide production, increased oxygen consumption,
      acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related
      to a hypermetabolic response.
    explanation: >-
      Muscle rigidity is one of the classic signs produced by the
      calcium-driven hypermetabolic response.
- name: Rhabdomyolysis
  description: >-
    Skeletal-muscle breakdown releases intracellular contents and contributes
    to renal and electrolyte complications.
  phenotype_term:
    preferred_term: Rhabdomyolysis
    term:
      id: HP:0003201
      label: Rhabdomyolysis
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The classic signs of MH include hyperthermia, tachycardia, tachypnea,
      increased carbon dioxide production, increased oxygen consumption,
      acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related
      to a hypermetabolic response.
    explanation: >-
      Rhabdomyolysis is listed as a classic manifestation of the acute MH
      crisis.
- name: Hyperkalemia
  description: >-
    Potassium release during the crisis contributes to arrhythmia risk and is a
    major laboratory abnormality during severe reactions.
  phenotype_term:
    preferred_term: Hyperkalemia
    term:
      id: HP:0002153
      label: Hyperkalemia
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The classic signs of MH include hyperthermia, tachycardia, tachypnea,
      increased carbon dioxide production, increased oxygen consumption,
      acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related
      to a hypermetabolic response.
    explanation: >-
      Hyperkalemia is listed as a classic laboratory feature of MH.
- name: Metabolic acidosis
  description: >-
    Increased skeletal-muscle metabolism and carbon dioxide production lead to
    acid-base derangement during the acute reaction.
  phenotype_term:
    preferred_term: Metabolic acidosis
    term:
      id: HP:0001942
      label: Metabolic acidosis
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The classic signs of MH include hyperthermia, tachycardia, tachypnea,
      increased carbon dioxide production, increased oxygen consumption,
      acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related
      to a hypermetabolic response.
    explanation: >-
      Acidosis is listed among the classic signs of the hypermetabolic MH
      response; the HPO term captures the metabolic component described in
      clinical summaries.
biochemical:
- name: End-tidal carbon dioxide
  presence: INCREASED
  context: >-
    Rising end-tidal carbon dioxide despite increased ventilation is an early
    diagnostic clue to the hypermetabolic skeletal-muscle crisis.
  biomarker_term:
    preferred_term: carbon dioxide
    term:
      id: CHEBI:16526
      label: carbon dioxide
  readouts:
  - target: Hypermetabolic skeletal muscle crisis
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Increased end-tidal carbon dioxide reports excess skeletal-muscle carbon dioxide production.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        An increase in end-tidal carbon dioxide despite increased minute
        ventilation provides an early diagnostic clue.
      explanation: This directly supports increased end-tidal carbon dioxide as an early diagnostic readout.
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      An increase in end-tidal carbon dioxide despite increased minute
      ventilation provides an early diagnostic clue.
    explanation: The review identifies increased end-tidal carbon dioxide as an early diagnostic clue.
  - reference: PMID:35414440
    reference_title: "Malignant Hyperthermia: A Killer If Ignored."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      characterized by rigidity of the masseter muscle, a high level of
      end-tidal carbon dioxide, and a sharp and persistent increase in body
      temperature.
    explanation: Human review supports high end-tidal carbon dioxide during the preclinical/early MH stage.
- name: Blood potassium
  presence: INCREASED
  context: >-
    Increased circulating potassium is the biochemical correlate of
    hyperkalemia during severe malignant hyperthermia crises.
  biomarker_term:
    preferred_term: potassium
    term:
      id: CHEBI:29103
      label: potassium(1+)
  readouts:
  - target: Hypermetabolic skeletal muscle crisis
    relationship: READOUT_OF
    direction: POSITIVE
    endpoint_context: DIAGNOSTIC
    interpretation: Hyperkalemia reports systemic electrolyte disturbance during the MH crisis.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        The classic signs of MH include hyperthermia, tachycardia, tachypnea,
        increased carbon dioxide production, increased oxygen consumption,
        acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all
        related to a hypermetabolic response.
      explanation: The review lists hyperkalemia among classic signs related to the hypermetabolic response.
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The classic signs of MH include hyperthermia, tachycardia, tachypnea,
      increased carbon dioxide production, increased oxygen consumption,
      acidosis, hyperkalaemia, muscle rigidity, and rhabdomyolysis, all related
      to a hypermetabolic response.
    explanation: Hyperkalemia in the classic-sign list supports increased blood potassium.
genetic:
- name: RYR1 susceptibility variants
  association: Causative
  gene_term:
    preferred_term: RYR1
    term:
      id: hgnc:10483
      label: RYR1
  notes: >-
    RYR1 is the dominant established malignant-hyperthermia susceptibility gene.
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Over 400 variants have been identified in the RYR1 gene located on
      chromosome 19q13.1, and at least 34 are causal for MH.
    explanation: >-
      Supports RYR1 as the major causal susceptibility gene.
- name: CACNA1S susceptibility variants
  association: Causative
  gene_term:
    preferred_term: CACNA1S
    term:
      id: hgnc:1397
      label: CACNA1S
  notes: >-
    CACNA1S contributes a smaller fraction of malignant-hyperthermia
    susceptibility than RYR1.
  evidence:
  - reference: PMID:32898259
    reference_title: Genomic Screening for Malignant Hyperthermia Susceptibility.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Malignant hyperthermia susceptibility is a heritable trait, primarily
      associated with variants in either the type 1 ryanodine receptor (RYR1)
      intracellular calcium channel or the alpha 1S subunit (CACNA1S) of the
      voltage-dependent L-type Ca2+ channel.
    explanation: >-
      Supports CACNA1S as an established susceptibility gene, while the wording
      preserves its lesser role relative to RYR1.
- name: STAC3-associated syndromic susceptibility
  association: Disease-associated
  gene_term:
    preferred_term: STAC3
    term:
      id: hgnc:28423
      label: STAC3
  notes: >-
    STAC3 is included as a qualified susceptibility gene because reported MH
    reactions are tied to biallelic variants and apparent congenital myopathy,
    rather than the common isolated susceptibility presentation.
  evidence:
  - reference: PMID:32898259
    reference_title: Genomic Screening for Malignant Hyperthermia Susceptibility.
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Another gene associated with malignant hyperthermia reactions is STAC3,
      although all the reported occurrences involve individuals with biallelic
      variants who have an apparent myopathy
    explanation: >-
      Supports a qualified STAC3 association while distinguishing syndromic
      biallelic myopathy-associated reactions from isolated MH susceptibility.
environmental:
- name: Triggering anesthetic exposure
  description: >-
    Volatile anesthetic gases and succinylcholine are the classic
    pharmacologic triggers; heat and exertion can rarely provoke related events
    in susceptible individuals.
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Malignant hyperthermia (MH) is a pharmacogenetic disorder of skeletal
      muscle that presents as a hypermetabolic response to potent volatile
      anesthetic gases such as halothane, sevoflurane, desflurane, isoflurane
      and the depolarizing muscle relaxant succinylcholine, and rarely, in
      humans, to stressors such as vigorous exercise and heat.
    explanation: >-
      Defines the key anesthetic triggers and rarer non-anesthetic stressors.
diagnosis:
- name: In vitro contracture testing
  description: >-
    Halothane-caffeine contracture testing of biopsied skeletal muscle remains
    the central physiologic diagnostic method for confirming susceptibility.
  diagnosis_term:
    preferred_term: diagnostic procedure
    term:
      id: MAXO:0000003
      label: diagnostic procedure
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Diagnostic testing involves the in vitro contracture response of biopsied
      muscle to halothane, caffeine, and in some centres ryanodine and
      4-chloro-m-cresol.
    explanation: >-
      Supports contracture testing as a definitive susceptibility diagnostic
      method.
- name: Genetic testing for susceptibility genes
  description: >-
    Genetic testing can identify pathogenic variants in established
    susceptibility genes, but negative testing does not exclude susceptibility
    because known genes and variant interpretations do not capture all cases.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: MAXO:0000127
      label: genetic testing
  evidence:
  - reference: PMID:35414440
    reference_title: "Malignant Hyperthermia: A Killer If Ignored."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Medical history, family history, clinical presentation, in vitro
      caffeine-halothane contracture testing (IVCT/CHCT) and genetic testing
      are commonly diagnostic methods of MH.
    explanation: >-
      Supports genetic testing as part of the diagnostic workup alongside
      history, presentation, and contracture testing.
treatments:
- name: Dantrolene
  description: >-
    Dantrolene is the specific emergency pharmacotherapy for malignant
    hyperthermia and should be administered rapidly once MH is diagnosed or
    strongly suspected.
  treatment_term:
    preferred_term: pharmacotherapy
    term:
      id: MAXO:0000058
      label: pharmacotherapy
    therapeutic_agent:
    - preferred_term: dantrolene
      term:
        id: CHEBI:4317
        label: dantrolene
  target_phenotypes:
  - preferred_term: Malignant hyperthermia
    term:
      id: HP:0002047
      label: Malignant hyperthermia
  target_mechanisms:
  - target: Trigger-dependent RyR1 calcium dysregulation
    treatment_effect: INHIBITS
    description: >-
      Dantrolene antagonizes the calcium-release crisis mechanism and is the
      specific emergency pharmacotherapy for malignant hyperthermia.
    evidence:
    - reference: PMID:26238698
      reference_title: "Malignant hyperthermia: a review."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Dantrolene sodium is a specific antagonist and should be available
        wherever general anesthesia is administered.
      explanation: The review supports dantrolene as the specific antagonist for the MH mechanism.
  evidence:
  - reference: PMID:26238698
    reference_title: "Malignant hyperthermia: a review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dantrolene sodium is a specific antagonist and should be available
      wherever general anesthesia is administered.
    explanation: >-
      Establishes dantrolene as the specific MH antagonist and perioperative
      emergency drug.
  - reference: PMID:36874927
    reference_title: Rapid Dantrolene Administration with Body Temperature Monitoring Is Associated with Decreased Mortality in Japanese Malignant Hyperthermia Events.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Dantrolene should be given as rapidly as possible once MH has been
      diagnosed. Beginning treatment at a more normal body temperature can
      prevent critical elevations associated with a worse prognosis.
    explanation: >-
      Retrospective clinical data support rapid dantrolene administration as a
      mortality-reducing intervention.
- name: Trigger discontinuation and supportive crisis care
  description: >-
    Crisis management includes immediate cessation of triggering agents,
    summoning expert support, hyperventilation and cooling as indicated, and
    correction of acidosis, hyperkalemia, arrhythmias, and renal complications.
  treatment_term:
    preferred_term: supportive care
    term:
      id: MAXO:0000950
      label: supportive care
  target_phenotypes:
  - preferred_term: Malignant hyperthermia
    term:
      id: HP:0002047
      label: Malignant hyperthermia
  target_mechanisms:
  - target: Trigger-dependent RyR1 calcium dysregulation
    treatment_effect: INHIBITS
    description: >-
      Removing volatile anesthetic or succinylcholine triggers stops further
      exposure of the susceptible calcium-release channel complex to the
      provoking stimulus.
    evidence:
    - reference: PMID:35414440
      reference_title: "Malignant Hyperthermia: A Killer If Ignored."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        As soon as the onset of MH is suspected, immediate cessation of exposure
        to stimuli, call for professional support, and access to dantrolene are
        the highest priorities.
      explanation: The review supports immediate trigger cessation as a top-priority mechanism-directed action.
  evidence:
  - reference: PMID:35414440
    reference_title: "Malignant Hyperthermia: A Killer If Ignored."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      As soon as the onset of MH is suspected, immediate cessation of exposure
      to stimuli, call for professional support, and access to dantrolene are
      the highest priorities.
    explanation: >-
      Supports immediate trigger discontinuation and coordinated supportive
      emergency care.
datasets: []
📚

References & Deep Research

References

1
PMID:20301325
Nonsyndromic Malignant Hyperthermia Susceptibility
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Disease Characteristics Research Template
Edison Scientific Literature 24 citations 2026-05-09T08:57:32.297883

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on: 1. Key concepts and definitions with current understanding 2. Recent developments and latest research (prioritize 2023-2024 sources) 3. Current applications and real-world implementations 4. Expert opinions and analysis from authoritative sources 5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available. Always prioritize recent, authoritative sources and provide specific citations for all major claims.

Disease Characteristics Research Template

Target Disease

  • Disease Name: Malignant hyperthermia of anesthesia
  • MONDO ID: (if available)
  • Category: Genetic

Research Objectives

Please provide a comprehensive research report on Malignant hyperthermia of anesthesia covering all of the disease characteristics listed below. This report will be used to populate a disease knowledge base entry. Be thorough and cite primary literature (PMID preferred) for all claims.

For each section, suggested databases/resources are listed. These are the first places you should search for information on each topic.

1. Disease Information

Search first: OMIM, Orphanet, ICD-10/ICD-11, MeSH, PubMed

  • What is the disease? Provide a concise overview.
  • What are the key identifiers? (OMIM, Orphanet, ICD-10/ICD-11, MeSH, Mondo)
  • What are the common synonyms and alternative names?
  • Is the information derived from individual patients (e.g., EHR) or aggregated disease-level resources?

2. Etiology

  • Disease Causal Factors: What are the primary causes? (genetic, environmental, infectious, mechanistic)
  • Risk Factors:

    Search first: PubMed, Cochrane Library, UpToDate, clinical guidelines, ClinVar, ClinGen, GWAS Catalog, PheGenI, CTD, CDC, WHO, epidemiological databases

  • Genetic risk factors (causal variants, susceptibility loci, modifier genes)
  • Environmental risk factors (toxins, lifestyle, occupational exposures, age, sex, family history)
  • Protective Factors:

    Search first: PubMed, Cochrane Library, clinical trial databases, GWAS Catalog, gnomAD, WHO, CDC, nutrition databases

  • Genetic protective factors (protective variants, modifier alleles)
  • Environmental protective factors (diet, lifestyle, exposures that reduce risk)
  • Gene-Environment Interactions: How do genetic and environmental factors interact to influence disease?

    Search first: CTD, PubMed, PheGenI, GxE databases

3. Phenotypes

Search first: HPO (Human Phenotype Ontology), OMIM, Orphanet, PubMed, clinicaltrials.gov, MedDRA, SNOMED CT, DECIPHER, LOINC

For each phenotype, provide: - Phenotype type: symptoms, clinical signs, physical manifestations, behavioral changes, or laboratory abnormalities

For symptoms/signs: HPO, OMIM, Orphanet, PubMed For behavioral changes: HPO, DSM, RDoC (Research Domain Criteria), PubMed For laboratory abnormalities: LOINC, SNOMED CT, LabTests Online, PubMed - Phenotype characteristics: Search first: OMIM, Orphanet, HPO, PubMed - Age of symptom onset (neonatal, childhood, adult-onset, late-onset) - Symptom severity (mild, moderate, severe, variable) - Symptom progression (stable, progressive, episodic, fluctuating) - Frequency among affected individuals (percentage or qualitative) - Quality of life impact: Effects on daily functioning and well-being (per-phenotype when possible) Search first: EQ-5D database, SF-36, WHO QOL databases, PubMed - Suggest HPO (Human Phenotype Ontology) terms for each phenotype

4. Genetic/Molecular Information

  • Causal Genes: Gene mutations or chromosomal abnormalities responsible for disease (gene symbols, OMIM IDs)

    Search first: OMIM, ClinVar, HGMD, Ensembl, NCBI Gene

  • Pathogenic Variants:
  • Affected genes (gene symbols, HGNC IDs) > Search first: OMIM, NCBI Gene, Ensembl, HGNC, UniProt, GeneCards
  • Variant classification (pathogenic, likely pathogenic, VUS per ACMG/AMP guidelines) > Search first: ClinVar, ClinGen, ACMG/AMP guidelines, VarSome
  • Variant type/class (missense, frameshift, nonsense, splice-site, structural)
  • Allele frequency in population databases > Search first: gnomAD, 1000 Genomes, ExAC, TOPMed, dbSNP
  • Somatic vs germline origin > Search first: COSMIC (somatic), ClinVar, ICGC, TCGA
  • Functional consequences (loss of function, gain of function, dominant negative)
  • Modifier Genes: Genes that modify disease severity or expression
  • Epigenetic Information: DNA methylation, histone modifications, chromatin changes affecting disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Chromosomal Abnormalities: Large-scale genetic changes (aneuploidy, translocations, inversions)

    Search first: DECIPHER, ClinVar, ECARUCA, UCSC Genome Browser

5. Environmental Information

  • Environmental Factors: Non-genetic contributing factors (toxins, radiation, pollution, occupational exposure)

    Search first: CTD (Comparative Toxicogenomics Database), TOXNET, PubMed, EPA databases

  • Lifestyle Factors: Behavioral factors (smoking, diet, exercise, alcohol consumption)

    Search first: CDC databases, WHO, PubMed, NHANES

  • Infectious Agents: If applicable, pathogens causing or triggering disease (bacteria, viruses, fungi, parasites)

    Search first: NCBI Taxonomy, ViPR, BV-BRC, MicrobeDB, GIDEON

6. Mechanism / Pathophysiology

  • Molecular Pathways: Specific signaling cascades or biochemical pathways involved (Wnt, MAPK, mTOR, PI3K-AKT, etc.)

    Search first: KEGG, Reactome, WikiPathways, PathBank, BioCyc

  • Cellular Processes: Cell-level mechanisms (apoptosis, autophagy, cell cycle dysregulation, inflammation, etc.)

    Search first: Gene Ontology (GO), Reactome, KEGG, PubMed

  • Protein Dysfunction: How protein structure or function is altered (misfolding, aggregation, loss of function, gain of function)

    Search first: UniProt, PDB (Protein Data Bank), InterPro, Pfam, AlphaFold

  • Metabolic Changes: Alterations in metabolic processes (energy metabolism, lipid metabolism, amino acid metabolism)

    Search first: KEGG, BioCyc, HMDB (Human Metabolome Database), BRENDA

  • Immune System Involvement: Role of immune response (autoimmunity, immunodeficiency, chronic inflammation)

    Search first: ImmPort, Immunome Database, IEDB, Gene Ontology

  • Tissue Damage Mechanisms: How tissues/ are injured (oxidative stress, ischemia, fibrosis, necrosis)

    Search first: PubMed, Gene Ontology, Reactome

  • Biochemical Abnormalities: Specific molecular defects (enzyme deficiencies, receptor dysfunction, ion channel defects)

    Search first: BRENDA, UniProt, KEGG, OMIM, PubMed

  • Epigenetic Changes: DNA methylation, histone modifications affecting gene expression in disease

    Search first: ENCODE, Roadmap Epigenomics, MethBase, DiseaseMeth

  • Molecular Profiling (if available):
  • Transcriptomics/gene expression changes > Search first: GEO (Gene Expression Omnibus), ArrayExpress, GTEx, Human Cell Atlas, SRA
  • Proteomics findings > Search first: PRIDE, ProteomeXchange, Human Protein Atlas, STRING, BioGRID
  • Metabolomics signatures > Search first: MetaboLights, Metabolomics Workbench, HMDB, METLIN
  • Lipidomics alterations > Search first: LIPID MAPS, SwissLipids, LipidHome, Metabolomics Workbench
  • Genomic structural features > Search first: UCSC Genome Browser, Ensembl, NCBI, dbVar, DGV
  • Advanced Technologies (if applicable):
  • Single-cell analysis findings (cell-type specific mechanisms, cellular heterogeneity) > Search first: Human Cell Atlas, Single Cell Portal, GEO, CELLxGENE
  • Spatial transcriptomics findings > Search first: GEO, Spatial Research, Vizgen, 10x Genomics data
  • Multi-omics integration results > Search first: TCGA, ICGC, cBioPortal, LinkedOmics, PubMed
  • Functional genomics screens (CRISPR, RNAi) > Search first: DepMap, GenomeRNAi, PubMed, BioGRID ORCS

For each mechanism, describe: - The causal chain from initial trigger to clinical manifestation - Which mechanisms are upstream vs downstream - What cell types and biological processes are involved - Suggest GO terms for biological processes and CL terms for cell types

7. Anatomical Structures Affected

  • Organ Level:
  • Primary organs directly affected
  • Secondary organ involvement (complications, secondary effects)
  • Body systems involved (cardiovascular, nervous, digestive, respiratory, endocrine, etc.)

    Search first: Uberon, FMA (Foundational Model of Anatomy), OMIM, HPO, ICD-11, MeSH, SNOMED CT

  • Tissue and Cell Level:
  • Specific tissue types affected (epithelial, connective, muscle, nervous)
  • Specific cell populations targeted (with Cell Ontology terms)

    Search first: Uberon, Human Protein Atlas, Cell Ontology, Human Cell Atlas, CellMarker, PanglaoDB

  • Subcellular Level:
  • Cellular compartments involved (mitochondria, nucleus, ER, lysosomes) (with GO Cellular Component terms)

    Search first: Gene Ontology (Cellular Component), UniProt, Human Protein Atlas

  • Localization:
  • Specific anatomical sites (with UBERON terms) > Search first: FMA, Uberon, NeuroNames (for brain), SNOMED CT
  • Lateralization (unilateral, bilateral, asymmetric) > Search first: HPO, clinical literature, imaging databases

8. Temporal Development

  • Onset:
  • Typical age of onset (congenital, pediatric, adult, geriatric)
  • Onset pattern (acute, subacute, chronic, insidious)

    Search first: OMIM, Orphanet, HPO, PubMed

  • Progression:
  • Disease stages (early, intermediate, advanced, end-stage) > Search first: Cancer Staging Manual (AJCC), WHO classifications, PubMed
  • Progression rate (rapid, slow, variable)
  • Disease course pattern (episodic, relapsing-remitting, progressive, stable)
  • Disease duration (self-limited, chronic lifelong)

    Search first: Disease registries, longitudinal cohort databases, natural history studies, PubMed, Orphanet, OMIM

  • Patterns:
  • Remission patterns (spontaneous, treatment-induced) > Search first: Clinical trial databases, disease registries, PubMed
  • Critical periods (time windows of vulnerability or opportunity for intervention) > Search first: PubMed, developmental biology databases, clinical guidelines

9. Inheritance and Population

  • Epidemiology:
  • Prevalence (cases per 100,000 at given time)
  • Incidence (new cases per 100,000 per year)

    Search first: Orphanet, CDC, WHO, GBD (Global Burden of Disease), national registries, SEER, disease registries

  • For Genetic Etiology:
  • Inheritance pattern (AD, AR, X-linked, mitochondrial, multifactorial, polygenic) > Search first: OMIM, Orphanet, ClinVar, GTR (Genetic Testing Registry)
  • Penetrance (complete, incomplete, age-dependent) > Search first: ClinVar, OMIM, PubMed, ClinGen
  • Expressivity (variable, consistent) > Search first: OMIM, ClinVar, PubMed
  • Genetic anticipation (increasing severity in successive generations) > Search first: OMIM, PubMed (especially for repeat expansion disorders)
  • Germline mosaicism > Search first: ClinVar, OMIM, genetic counseling literature, PubMed
  • Founder effects (population-specific mutations) > Search first: gnomAD, population genetics databases, PubMed
  • Consanguinity role > Search first: OMIM, population studies, genetic counseling resources
  • Carrier frequency > Search first: gnomAD, carrier screening databases, GeneReviews, GTR
  • Population Demographics:
  • Affected populations (ethnic or demographic groups with higher prevalence) > Search first: gnomAD, 1000 Genomes, PAGE Study, PubMed, population registries
  • Geographic distribution (endemic areas, regional variation) > Search first: WHO, CDC, GBD, Orphanet, geographic epidemiology databases
  • Geographic distribution of specific variants
  • Sex ratio (male:female) > Search first: Disease registries, OMIM, PubMed, epidemiological databases
  • Age distribution of affected individuals > Search first: CDC, disease registries, SEER, Orphanet

10. Diagnostics

  • Clinical Tests:
  • Laboratory tests (blood, urine, tissue chemistry, specific enzyme assays) > Search first: LOINC, LabTests Online, PubMed
  • Biomarkers (proteins, metabolites, genetic markers, circulating biomarkers) > Search first: FDA Biomarker List, BEST (Biomarkers, EndpointS, and other Tools), PubMed
  • Imaging studies (X-ray, CT, MRI, PET, ultrasound) > Search first: RadLex, DICOM, Radiopaedia, imaging databases
  • Functional tests (pulmonary function, cardiac stress tests) > Search first: LOINC, clinical guidelines, PubMed
  • Electrophysiology (EEG, EMG, ECG, nerve conduction studies) > Search first: LOINC, clinical neurophysiology databases, PubMed
  • Biopsy findings (histopathology, immunohistochemistry) > Search first: SNOMED CT, College of American Pathologists resources, PubMed
  • Pathology findings (microscopic examination) > Search first: SNOMED CT, Digital Pathology databases, PubMed
  • Genetic Testing:

    Search first: GTR (Genetic Testing Registry), GeneReviews, ClinGen

  • Overview of recommended genetic testing approach
  • Whole genome sequencing (WGS) utility > Search first: GTR, ClinVar, GEL (Genomics England), gnomAD
  • Whole exome sequencing (WES) utility > Search first: GTR, ClinVar, OMIM, GeneMatcher
  • Gene panels (which panels, which genes) > Search first: GTR, ClinVar, laboratory-specific databases
  • Single gene testing > Search first: GTR, ClinVar, OMIM, GeneReviews
  • Chromosomal microarray (CMA) > Search first: DECIPHER, ClinVar, dbVar, ECARUCA
  • Karyotyping > Search first: Chromosome Abnormality Database, ClinVar, cytogenetics resources
  • FISH > Search first: ClinVar, cytogenetics databases, PubMed
  • Mitochondrial DNA testing > Search first: MITOMAP, MSeqDR, ClinVar, GTR
  • Repeat expansion testing > Search first: GTR, ClinVar, repeat expansion databases, PubMed
  • Omics-Based Diagnostics (if applicable):
  • RNA sequencing / transcriptomics > Search first: GEO, ArrayExpress, GTEx, RNA-seq databases
  • Proteomics > Search first: PRIDE, ProteomeXchange, FDA Biomarker database
  • Metabolomics > Search first: MetaboLights, Metabolomics Workbench, HMDB
  • Epigenomics > Search first: GEO, ENCODE, Roadmap Epigenomics, MethBase
  • Liquid biopsy > Search first: COSMIC, ClinVar, liquid biopsy databases, PubMed
  • Clinical Criteria:
  • Standardized diagnostic criteria (DSM, ICD, society guidelines) > Search first: DSM-5, ICD-11, clinical society guidelines, UpToDate
  • Differential diagnosis (other conditions to rule out, with distinguishing features) > Search first: DynaMed, UpToDate, clinical decision support systems
  • Screening:
  • Screening methods for asymptomatic individuals (newborn screening, carrier screening, cascade screening) > Search first: ACMG recommendations, CDC newborn screening, GTR

11. Outcome/Prognosis

  • Survival and Mortality:
  • Survival rate (5-year, 10-year, overall) > Search first: SEER, cancer registries, disease-specific registries, PubMed
  • Life expectancy (with and without treatment if applicable) > Search first: Orphanet, disease registries, actuarial databases, PubMed
  • Mortality rate > Search first: CDC, WHO, GBD, national mortality databases
  • Disease-specific mortality (deaths directly attributable to disease) > Search first: Disease registries, CDC Wonder, GBD, PubMed
  • Morbidity and Function:
  • Morbidity (disease-related disability and health impacts) > Search first: GBD, WHO, disability databases, PubMed
  • Disability outcomes (long-term functional impairments) > Search first: ICF (International Classification of Functioning), disability registries
  • Quality of life measures (EQ-5D, SF-36, PROMIS, disease-specific tools) > Search first: EQ-5D database, SF-36, PROMIS, PubMed
  • Disease Course:
  • Complications (secondary problems: infections, organ failure, etc.) > Search first: ICD codes, disease registries, clinical databases, PubMed
  • Recovery potential (likelihood and extent of recovery, with vs without treatment) > Search first: Natural history studies, rehabilitation databases, PubMed
  • Prediction:
  • Prognostic factors (age, disease severity, biomarkers, treatment response) > Search first: Prognostic models databases, clinical calculators, PubMed
  • Prognostic biomarkers (molecular markers predicting disease course) > Search first: FDA Biomarker database, PubMed, cancer prognostic databases

12. Treatment

  • Pharmacotherapy:
  • Pharmacological treatments (drug names, drug classes, mechanisms of action) > Search first: DrugBank, RxNorm, ATC classification, DailyMed, FDA databases
  • Pharmacogenomics (how genetic variants affect drug metabolism, efficacy, toxicity) > Search first: PharmGKB, CPIC (Clinical Pharmacogenetics), FDA Table of PGx Biomarkers
  • Advanced Therapeutics:
  • Gene therapy (viral vectors, CRISPR, gene replacement, gene editing) > Search first: ClinicalTrials.gov, FDA gene therapy database, ASGCT resources
  • Cell therapy (stem cell transplant, CAR-T, cellular therapeutics) > Search first: ClinicalTrials.gov, FDA cell therapy database, FACT standards
  • RNA-based therapies (ASOs, siRNA, mRNA therapies) > Search first: ClinicalTrials.gov, FDA approvals, PubMed
  • Targeted therapies (treatments directed at specific molecular targets) > Search first: My Cancer Genome, OncoKB, ClinicalTrials.gov, FDA approvals
  • Immunotherapies (checkpoint inhibitors, monoclonal antibodies) > Search first: Cancer Immunotherapy Database, FDA approvals, ClinicalTrials.gov
  • Surgical and Interventional:
  • Surgical interventions (types of surgery, timing, outcomes) > Search first: CPT codes, surgical registries, clinical guidelines, PubMed
  • Supportive and Rehabilitative:
  • Supportive care (symptom management, pain control, nutrition) > Search first: Clinical guidelines, Cochrane Library, PubMed
  • Rehabilitation (physical therapy, occupational therapy, speech therapy) > Search first: Rehabilitation medicine databases, clinical guidelines, PubMed
  • Experimental:
  • Experimental treatments in clinical trials (with NCT identifiers if available) > Search first: ClinicalTrials.gov, EU Clinical Trials Register, WHO ICTRP
  • Treatment Outcomes:
  • Treatment response rates > Search first: Clinical trial databases, FDA reviews, systematic reviews, PubMed
  • Side effects and adverse events > Search first: FDA Adverse Event Reporting System (FAERS), MedWatch, PubMed
  • Treatment Strategy:
  • Treatment algorithms (clinical pathways, decision trees) > Search first: Clinical practice guidelines, NCCN Guidelines, UpToDate
  • Combination therapies > Search first: ClinicalTrials.gov, treatment guidelines, PubMed
  • Personalized medicine approaches (genotype-guided treatment) > Search first: My Cancer Genome, CIViC, PharmGKB, precision medicine databases

For each treatment, suggest MAXO (Medical Action Ontology) terms where applicable.

13. Prevention

  • Prevention Levels:
  • Primary prevention (preventing disease occurrence: vaccination, risk factor modification) > Search first: CDC, WHO, USPSTF recommendations, Cochrane Library
  • Secondary prevention (early detection and treatment: screening programs, early intervention) > Search first: USPSTF, CDC screening guidelines, WHO
  • Tertiary prevention (preventing complications in those with disease) > Search first: Clinical guidelines, disease management protocols, PubMed
  • Immunization: Vaccine strategies (if applicable)

    Search first: CDC vaccine schedules, WHO immunization, FDA vaccine database

  • Screening and Early Detection:
  • Screening programs (population-based: newborn screening, cancer screening) > Search first: CDC screening programs, USPSTF, cancer screening databases
  • Genetic screening (carrier screening, preimplantation genetic diagnosis, prenatal testing) > Search first: ACMG recommendations, ACOG guidelines, GTR
  • Risk stratification (identifying high-risk individuals for targeted prevention) > Search first: Risk prediction models, clinical calculators, PubMed
  • Behavioral Interventions: Lifestyle modifications to reduce risk

    Search first: CDC, WHO, behavioral intervention databases, Cochrane Library

  • Counseling: Genetic counseling (risk assessment, family planning guidance)

    Search first: NSGC resources, ACMG guidelines, GeneReviews

  • Public Health:
  • Public health interventions (sanitation, vector control, health education) > Search first: CDC, WHO, public health databases, PubMed
  • Environmental interventions (reducing environmental risk factors) > Search first: EPA databases, WHO environmental health, PubMed
  • Prophylaxis: Preventive medications or procedures

    Search first: Clinical guidelines, FDA approvals, PubMed

14. Other Species / Natural Disease

  • Taxonomy: Species affected (with NCBI Taxon identifiers)

    Search first: NCBI Taxonomy

  • Breed: Specific breeds affected (with VBO identifiers if applicable)

    Search first: VBO (Vertebrate Breed Ontology)

  • Gene: Orthologous genes in other species (with NCBI Gene IDs)

    Search first: NCBI Gene

  • Natural Disease:
  • Naturally occurring disease in other species (companion animals, wildlife) > Search first: OMIA (Online Mendelian Inheritance in Animals), VetCompass, PubMed
  • Veterinary relevance and importance in animal health > Search first: OMIA, veterinary databases, PubMed
  • Comparative Biology:
  • Comparative pathology (similarities and differences across species) > Search first: OMIA, comparative pathology databases, PubMed
  • Evolutionary conservation of disease mechanisms > Search first: HomoloGene, OrthoMCL, Alliance of Genome Resources
  • Transmission (if applicable):
  • Zoonotic potential > Search first: CDC zoonotic diseases, WHO zoonoses, GIDEON
  • Cross-species susceptibility > Search first: NCBI Taxonomy, veterinary databases, PubMed

15. Model Organisms

  • Model Types:
  • Model organism type (mammalian, invertebrate, cellular, in vitro) > Search first: Alliance of Genome Resources, model organism databases
  • Specific model systems (mouse, rat, zebrafish, Drosophila, C. elegans, yeast, cell lines, organoids, iPSCs) > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, SGD, ATCC, Cellosaurus
  • Induced models (drug treatment, surgical intervention, environmental manipulation) > Search first: MGI, model organism databases, PubMed
  • Genetic Models:
  • Types available (knockout, knock-in, transgenic, conditional, humanized) > Search first: MGI, IMPC, KOMP, EuMMCR, IMSR
  • Model Characteristics:
  • Phenotype recapitulation (how well model reproduces human disease features) > Search first: Model organism databases, comparative studies, PubMed
  • Model limitations (aspects of human disease not captured) > Search first: Model organism databases, PubMed, review articles
  • Applications:
  • Research applications (what aspects of disease can be studied) > Search first: Model organism databases, PubMed
  • Resources:
  • Model databases > Search first: MGI, RGD, ZFIN, FlyBase, WormBase, IMSR, EMMA, MMRRC

Citation Requirements

  • Cite primary literature (PMID preferred) for all mechanistic and clinical claims
  • Prioritize recent reviews and landmark papers
  • Include direct quotes from abstracts where possible to support key statements
  • Distinguish evidence source types: human clinical, model organism, in vitro, computational

Output Format

Structure your response as a comprehensive narrative organized by the sections above. For each section, provide: - Factual content with specific details (numbers, percentages, gene names, variant nomenclature) - Ontology term suggestions (HPO, GO, CL, UBERON, CHEBI, MAXO, MONDO) where applicable - Evidence citations with PMIDs - Direct quotes from abstracts to support key claims - Clear indication when information is not available or not applicable for this disease

This report will be used to populate a disease knowledge base entry with: - Pathophysiology descriptions with causal chains - Gene/protein annotations (HGNC, GO terms) - Phenotype associations (HP terms) with frequencies - Cell type involvement (CL terms) - Anatomical locations (UBERON terms) - Chemical entities (CHEBI terms) - Treatment annotations (MAXO terms) - Evidence items with PMIDs and exact abstract quotes - Epidemiology, prognosis, diagnostic, and prevention information - Animal model descriptions with phenotype recapitulation details

Comprehensive Research Report: Malignant hyperthermia of anesthesia (malignant hyperthermia susceptibility)

Executive summary

Malignant hyperthermia (MH) of anesthesia—often discussed as malignant hyperthermia susceptibility (MHS)—is a rare, potentially fatal pharmacogenetic disorder of skeletal muscle excitation–contraction coupling. Exposure to triggering anesthetics (volatile halogenated agents and/or succinylcholine) causes uncontrolled intracellular Ca2+ release, producing a hypermetabolic crisis with hypercapnia, acidosis, hyperkalemia, muscle rigidity, rhabdomyolysis, hyperthermia, and multiorgan failure if untreated (rosenberg2015malignanthyperthermiaa pages 1-2, frassanito2023realevidenceand pages 1-3). Mortality has decreased markedly since dantrolene became available, but delayed recognition and limited drug availability remain major real-world barriers (rosenberg2015malignanthyperthermiaa pages 1-2, toyota2023rapiddantroleneadministration pages 6-6).

Topic Concise summary Strongest supporting citation IDs
Core definition Malignant hyperthermia susceptibility (MHS) is a rare, life-threatening pharmacogenetic disorder of skeletal muscle excitation–contraction coupling in which exposure to triggering anesthetics causes uncontrolled intracellular Ca2+ release, hypermetabolism, rhabdomyolysis, and heat production. (frassanito2023realevidenceand pages 1-3, rosenberg2015malignanthyperthermiaa pages 1-2)
Main triggers Major anesthetic triggers are volatile halogenated anesthetics (desflurane, isoflurane, sevoflurane, halothane) and succinylcholine; non-anesthetic stressors such as exercise and heat can provoke MH-like events in some susceptible individuals. (frassanito2023realevidenceand pages 1-3, rosenberg2015malignanthyperthermiaa pages 1-2, rosenberg2015malignanthyperthermiaa pages 12-13)
Key genes Definitive/major genes are RYR1, CACNA1S, and STAC3; RYR1 is the predominant gene, explaining most genetically resolved cases, while CACNA1S accounts for a small minority and STAC3 is classically linked to recessive syndromic myopathy with MH risk. (biesecker2020genomicscreeningfor pages 1-2, paranjpe2024candidatelociin pages 19-24, frassanito2023realevidenceand pages 1-3)
Inheritance In humans, MHS is usually autosomal dominant with incomplete penetrance and variable expressivity; in pigs, malignant hyperthermia/porcine stress syndrome is classically autosomal recessive. (frassanito2023realevidenceand pages 1-3, rosenberg2015malignanthyperthermiaa pages 1-2, riazi2018malignanthyperthermiain pages 1-3)
Key diagnostic tests Gold-standard functional tests are IVCT/CHCT on biopsied muscle; clinical diagnosis can be supported by the Larach clinical grading scale when definitive testing is not immediately available; genetic testing is useful but does not exclude disease if negative. (bin2022malignanthyperthermiaa pages 5-7, biesecker2020genomicscreeningfor pages 1-2, frassanito2023realevidenceand pages 9-10)
Hallmark clinical/lab features Typical features include rapidly rising end-tidal CO2, tachycardia, muscle rigidity or masseter spasm, hyperthermia, metabolic and respiratory acidosis, hyperkalemia, rhabdomyolysis, myoglobinuria, and elevated creatine kinase. (rosenberg2015malignanthyperthermiaa pages 1-2, rosenberg2015malignanthyperthermiaa pages 2-4, frassanito2023realevidenceand pages 1-3)
Epidemiology numbers Reported MH reaction incidence during anesthesia ranges roughly from 1:10,000 to 1:250,000 anesthetics; prevalence of underlying genetic susceptibility has been estimated as high as ~1 in 400 in some sources, though other genomic estimates are lower/higher depending on method. (rosenberg2015malignanthyperthermiaa pages 1-2, biesecker2020genomicscreeningfor pages 1-2, riazi2018malignanthyperthermiain pages 1-3)
Pediatric vs adult incidence Children are disproportionately affected: one 2023 review states pediatric incidence is about five-fold higher than in adults, with estimated incidence about 1:10,000 in children versus 1:50,000 in adults; mean reaction age is ~18.3 years. (frassanito2023realevidenceand pages 1-3, rosenberg2015malignanthyperthermiaa pages 2-4, rosenberg2015malignanthyperthermiaa pages 1-2)
Mortality trends Mortality has fallen dramatically with recognition and dantrolene availability: historical estimates were ~70–80%, declining to <5% by 2006 in one major review; more recent series/reviews cite mortality in the low single digits to about 10% depending on cohort and treatment speed. (rosenberg2015malignanthyperthermiaa pages 1-2, biesecker2020genomicscreeningfor pages 1-2, toyota2023rapiddantroleneadministration pages 6-6)
Acute management Immediate actions are to stop triggering agents, call for help, hyperventilate with 100% oxygen, switch to non-triggering anesthesia/TIVA, administer IV dantrolene promptly, cool aggressively as indicated, and treat acidosis, hyperkalemia, arrhythmias, and renal complications. (frassanito2023realevidenceand pages 9-10, banu2026advancesinmalignant pages 1-2, toyota2023rapiddantroleneadministration pages 6-6)
Dantrolene evidence Dantrolene is the specific antidote; delayed administration is associated with worse outcomes, and in a 2023 Japanese cohort mortality was higher without dantrolene and worse when time to dantrolene and temperature at dosing were greater. (toyota2023rapiddantroleneadministration pages 6-6, rosenberg2015malignanthyperthermiaa pages 1-2)
Prevention / trigger-free anesthesia For known or suspected MHS, trigger-free anesthesia eliminates perioperative trigger risk; safe approaches include regional anesthesia and TIVA, with continuous EtCO2 and core-temperature monitoring throughout the perioperative period. (frassanito2023realevidenceand pages 9-10, frassanito2023realevidenceand pages 1-3)
Anesthesia machine preparation / activated charcoal filters Vaporizers should be removed, circuits and soda lime changed, and the machine flushed per manufacturer guidance; activated charcoal filters on inspiratory and expiratory limbs can reduce residual volatile concentration to <5 ppm within 2–3 min and maintain low levels for up to 12 h with fresh gas flow ≥3 L/min after a brief high-flow flush. (frassanito2023realevidenceand pages 9-10, frassanito2023realevidenceand pages 13-15)

Table: This table condenses the highest-yield clinical and molecular facts about malignant hyperthermia susceptibility, including diagnosis, epidemiology, and perioperative management. It is useful as a rapid reference for building the full disease knowledge base entry.

1. Disease information

1.1 Overview (definition)

Definition (current understanding): MH is “a rare but life-threatening pharmacogenetic disorder triggered by exposure to specific anesthetic agents” (Frassanito et al., J Clin Med, published 2023-06-06; DOI:10.3390/jcm12123869) (frassanito2023realevidenceand pages 1-3). A large authoritative review similarly defines MH as “a pharmacogenetic disorder of skeletal muscle” presenting as “a hypermetabolic response to potent volatile anesthetic gases… and the depolarizing muscle relaxant succinylcholine” (Rosenberg et al., Orphanet J Rare Dis, published 2015-08-13; DOI:10.1186/s13023-015-0310-1) (rosenberg2015malignanthyperthermiaa pages 1-2).

1.2 Key identifiers / ontology

Note: The present tool run retrieved and cited peer-reviewed literature; it did not retrieve structured disease-ontology records (e.g., MONDO browser pages). Therefore, MONDO ID is not confirmed from primary context.

  • OMIM (disease concept): MH susceptibility locus is commonly referred to as MHS1 / OMIM #145600 in the genetics literature (paranjpe2024candidatelociin pages 19-24).
  • Genes (OMIM gene entries referenced in context): RYR1 is referenced with OMIM-style gene annotation and location 19q13.1 in major reviews (rosenberg2015malignanthyperthermiaa pages 1-2).
  • GeneReviews (authoritative clinical genetics resource): A 2023 review cites GeneReviews® “Malignant Hyperthermia Susceptibility” as a standard reference (frassanito2023realevidenceand pages 13-15).
  • Other clinical classification systems (ICD/MeSH/Orphanet): Not extractable from the current evidence corpus with citable IDs; should be added from OMIM/Orphanet/ICD/MeSH directly in a subsequent structured database query.

1.3 Synonyms / alternative names

Common names in the retrieved evidence: - Malignant hyperthermia (MH) (rosenberg2015malignanthyperthermiaa pages 1-2) - Malignant hyperthermia susceptibility (MHS) (frassanito2023realevidenceand pages 1-3) - Anesthesia-related malignant hyperthermia / malignant hyperthermia due to anesthesia (implicit framing in perioperative reviews) (ruta2025perioperativenursingof pages 2-3)

1.4 Evidence source type

Most information here is derived from aggregated disease-level resources (narrative reviews, guideline-oriented reviews) (rosenberg2015malignanthyperthermiaa pages 1-2, frassanito2023realevidenceand pages 1-3) plus observational registry/cohort analyses informing risk and outcomes (e.g., dantrolene timing vs mortality) (toyota2023rapiddantroleneadministration pages 6-6).

2. Etiology

2.1 Disease causal factors

Primary causal factor (genetic/pharmacogenetic): MH is caused by inherited abnormalities in skeletal muscle excitation–contraction coupling that remain clinically silent until a trigger exposure. A 2015 authoritative review states “In most cases, the syndrome is caused by a defect in the ryanodine receptor” (rosenberg2015malignanthyperthermiaa pages 1-2).

Trigger exposure (environmental/pharmacologic): The principal environmental cause of an episode is exposure to triggering anesthetic agents: volatile halogenated anesthetics and succinylcholine (rosenberg2015malignanthyperthermiaa pages 1-2, frassanito2023realevidenceand pages 1-3).

2.2 Risk factors

Genetic risk factors

  • Major susceptibility genes: RYR1 (predominant), CACNA1S (minor fraction), and STAC3 (notably associated with recessive syndromic myopathy with MH risk) (biesecker2020genomicscreeningfor pages 1-2, frassanito2023realevidenceand pages 1-3).
  • Variant heterogeneity: Rosenberg et al. reports “Over 400 variants have been identified in the RYR1 gene… and at least 34 are causal for MH,” while “Less than 1% of variants have been found in CACNA1S but not all of these are causal” (rosenberg2015malignanthyperthermiaa pages 1-2).
  • Incomplete penetrance/variable expressivity: Pediatric review notes MHS is autosomal dominant with incomplete penetrance (frassanito2023realevidenceand pages 1-3), consistent with post-genomics perspectives emphasizing discordance between variant prevalence and clinical incidence (riazi2018malignanthyperthermiain pages 1-3).

Environmental/pharmacologic risk factors

  • Anesthetic triggers: volatile anesthetics and succinylcholine (rosenberg2015malignanthyperthermiaa pages 1-2, frassanito2023realevidenceand pages 1-3).
  • Non-anesthetic stressors: vigorous exercise and heat are described as rare triggers in humans (rosenberg2015malignanthyperthermiaa pages 1-2, rosenberg2015malignanthyperthermiaa pages 12-13).

2.3 Protective factors

  • Primary protection is trigger avoidance: For suspected/confirmed MHS, the “mere avoidance of triggering substances eliminates the risk of developing an MH event” perioperatively (frassanito2023realevidenceand pages 9-10).

2.4 Gene–environment interaction

The core interaction is genotype-dependent vulnerability + drug exposure (volatile anesthetics/succinylcholine) leading to crisis. Additional stressors (exercise/heat) are described in susceptible individuals, supporting broader gene–environment coupling beyond the operating room (rosenberg2015malignanthyperthermiaa pages 1-2, rosenberg2015malignanthyperthermiaa pages 12-13).

3. Phenotypes

3.1 Acute MH crisis phenotypes (perioperative)

Core clinical signs (from authoritative review): hyperthermia, tachycardia, tachypnea, increased CO2 production (hypercapnia/raised end-tidal CO2), increased oxygen consumption, acidosis, hyperkalemia, muscle rigidity, and rhabdomyolysis (rosenberg2015malignanthyperthermiaa pages 1-2).

Early clue: “An increase in end-tidal carbon dioxide despite increased minute ventilation provides an early diagnostic clue” (rosenberg2015malignanthyperthermiaa pages 1-2).

Common laboratory abnormalities: hyperkalemia and markedly elevated creatine kinase with rhabdomyolysis/myoglobinuria are central (rosenberg2015malignanthyperthermiaa pages 1-2). In masseter rigidity presentations, very high CK can support susceptibility in some cohorts (paranjpe2024candidatelociin pages 19-24).

3.2 Age of onset, severity, progression

  • Onset pattern: typically acute/fulminant after trigger exposure during anesthesia (rosenberg2015malignanthyperthermiaa pages 1-2).
  • Age distribution: reactions occur across the lifespan; a major review reports earliest confirmed 6 months and oldest 78 years; mean age ~18.3 years; children <15 represent ~52.1% of reactions (rosenberg2015malignanthyperthermiaa pages 2-4).
  • Severity: ranges from abortive/early presentations (e.g., masseter spasm) to fulminant hypermetabolic crisis with multiorgan failure (ruta2025perioperativenursingof pages 2-3, rosenberg2015malignanthyperthermiaa pages 1-2).

3.3 Quality-of-life impact

Outside anesthesia, some MHS individuals may have chronic myopathic manifestations (e.g., myalgia, fatigue, episodic rhabdomyolysis), which can affect daily functioning; these phenotypes are noted in disease discussions of MHS and RyR1-related disease (rosenberg2015malignanthyperthermiaa pages 12-13).

3.4 Suggested HPO terms (examples; to be verified/expanded against HPO)

Based on manifestations described in the cited clinical literature: - Hyperthermia (HP:0001945) (rosenberg2015malignanthyperthermiaa pages 1-2) - Hypercapnia / Increased end-tidal CO2 (HP:0001942; proxy term) (rosenberg2015malignanthyperthermiaa pages 1-2) - Metabolic acidosis (HP:0001940) (rosenberg2015malignanthyperthermiaa pages 1-2) - Tachycardia (HP:0001649) (rosenberg2015malignanthyperthermiaa pages 1-2) - Muscle rigidity (HP:0001276) (rosenberg2015malignanthyperthermiaa pages 1-2) - Rhabdomyolysis (HP:0003201) (rosenberg2015malignanthyperthermiaa pages 1-2) - Hyperkalemia (HP:0002153) (rosenberg2015malignanthyperthermiaa pages 1-2) - Myoglobinuria (HP:0002928) (rosenberg2015malignanthyperthermiaa pages 1-2)

4. Genetic / molecular information

4.1 Causal genes (and role)

  • RYR1 (ryanodine receptor 1): dominant MH susceptibility gene and the principal cause in most genetically resolved cases (rosenberg2015malignanthyperthermiaa pages 1-2, biesecker2020genomicscreeningfor pages 1-2).
  • CACNA1S (Cav1.1 / DHPR α1S): less common contributor to MH susceptibility (rosenberg2015malignanthyperthermiaa pages 1-2, biesecker2020genomicscreeningfor pages 1-2).
  • STAC3: implicated in MH susceptibility particularly in the context of congenital myopathy (Native American myopathy), typically recessive (biesecker2020genomicscreeningfor pages 1-2, paranjpe2024candidatelociin pages 19-24).

4.2 Pathogenic variants and functional consequences

  • Variant burden: RYR1 has >400 reported variants with a smaller subset accepted as causal/diagnostically actionable; CACNA1S contributes a small fraction (rosenberg2015malignanthyperthermiaa pages 1-2).
  • Functional consequence: sustained/inappropriate intracellular Ca2+ release leading to ATP depletion, thermogenesis, and muscle breakdown is the unifying mechanism (frassanito2023realevidenceand pages 1-3).

4.3 Modifier genes / polygenic models

A threshold/multifactorial model has been proposed to explain disparities between variant prevalence and observed clinical incidence (riazi2018malignanthyperthermiain pages 1-3, paranjpe2024candidatelociin pages 19-24). This supports the idea that additional genetic modifiers and/or environmental cofactors influence clinical expression.

4.4 Epigenetic information

Discordance between genotype and phenotype has been attributed in part to epigenetic changes at the RYR1 locus (e.g., altered muscle-specific microRNAs and gene silencing) in a major review (rosenberg2015malignanthyperthermiaa pages 13-14).

5. Environmental information

5.1 Environmental/iatrogenic triggers

  • Volatile halogenated anesthetics (desflurane, isoflurane, sevoflurane, halothane) and succinylcholine are primary triggers (frassanito2023realevidenceand pages 1-3, rosenberg2015malignanthyperthermiaa pages 1-2).
  • Stressors (exercise/heat) may trigger MH-like events in susceptible individuals (rosenberg2015malignanthyperthermiaa pages 1-2).

5.2 Lifestyle factors / infectious agents

No specific lifestyle or infectious causes are established as primary causes in the cited evidence; rather, they may modulate risk in susceptible individuals, and consensus is limited (rosenberg2015malignanthyperthermiaa pages 13-14).

6. Mechanism / pathophysiology

6.1 Causal chain (trigger → molecular event → phenotype)

  1. Trigger exposure (volatile anesthetics and/or succinylcholine) in a genetically susceptible individual (frassanito2023realevidenceand pages 1-3).
  2. Excitation–contraction coupling dysfunction leads to excessive SR Ca2+ release (RYR1/Cav1.1/STAC3 pathway) (frassanito2023realevidenceand pages 1-3, riazi2018malignanthyperthermiain pages 1-3).
  3. Sustained myoplasmic Ca2+ elevation drives sustained contraction, ATP consumption, heat production, CO2 production, acidosis, and muscle breakdown (rhabdomyolysis) (frassanito2023realevidenceand pages 1-3, rosenberg2015malignanthyperthermiaa pages 1-2).
  4. Downstream systemic complications: hyperkalemia, arrhythmia, acute kidney injury (from myoglobin), disseminated intravascular coagulation at extreme temperatures, and multiorgan failure (rosenberg2015malignanthyperthermiaa pages 2-4).

6.2 Molecular pathways / cellular processes (suggestions)

  • GO biological process candidates: calcium ion homeostasis; regulation of cytosolic calcium ion concentration; skeletal muscle contraction; ATP metabolic process; response to heat; cell death/necrosis secondary to metabolic crisis (supported conceptually by mechanistic descriptions) (frassanito2023realevidenceand pages 1-3, riazi2018malignanthyperthermiain pages 1-3).
  • Cell types (CL suggestions): skeletal muscle myocytes (e.g., skeletal muscle fiber cell) are primary affected cells (rosenberg2015malignanthyperthermiaa pages 1-2).

6.3 Visual evidence (pathway schematic)

Figure evidence for excitation–contraction coupling dysfunction and dantrolene mechanism is available from a 2023 review figure (frassanito2023realevidenceand media 1892a3c8).

7. Anatomical structures affected

7.1 Organ and system level

  • Primary tissue: skeletal muscle (hypermetabolic crisis originates in myocytes) (rosenberg2015malignanthyperthermiaa pages 1-2, frassanito2023realevidenceand pages 1-3).
  • Secondary organ involvement (complications): cardiovascular system (tachycardia/arrhythmia), kidneys (myoglobin-associated injury), systemic coagulation abnormalities at extreme hyperthermia (rosenberg2015malignanthyperthermiaa pages 2-4).

7.2 Subcellular localization (mechanistic)

  • Sarcoplasmic reticulum Ca2+ release channel complex (RyR1) is central (frassanito2023realevidenceand pages 1-3).

7.3 Suggested anatomy ontology terms

  • UBERON: skeletal muscle tissue (UBERON:0001134)

8. Temporal development

8.1 Onset

  • Acute onset typically occurs intraoperatively or in the early postoperative period after trigger exposure (rosenberg2015malignanthyperthermiaa pages 1-2).

8.2 Course / progression

  • Rapid progression to hypermetabolic crisis if triggers are not stopped and dantrolene/supportive care not instituted (rosenberg2015malignanthyperthermiaa pages 1-2).
  • Potential recurrence: monitoring for recurrence after initial control is emphasized in management discussions (banu2026advancesinmalignant pages 1-2).

9. Inheritance and population

9.1 Inheritance

  • Humans: typically autosomal dominant, with incomplete penetrance and variable expressivity (rosenberg2015malignanthyperthermiaa pages 1-2, frassanito2023realevidenceand pages 1-3).
  • Pigs: classically autosomal recessive in porcine stress syndrome/porcine MH (rosenberg2015malignanthyperthermiaa pages 1-2).

9.2 Epidemiology (statistics)

Incidence (during anesthesia): A major review reports “The incidence of MH reactions ranges from 1:10,000 to 1: 250,000 anesthetics” (rosenberg2015malignanthyperthermiaa pages 1-2).

Genetic prevalence: The same review states “the prevalence of the genetic abnormalities may be as great as one in 400 individuals” (rosenberg2015malignanthyperthermiaa pages 1-2). (Genomics-oriented reviews note substantial variability in prevalence estimates depending on ascertainment and variant curation) (biesecker2020genomicscreeningfor pages 1-2, riazi2018malignanthyperthermiain pages 1-3).

Age/sex distribution: Male predominance (~2:1) and pediatric overrepresentation are reported in major summaries (rosenberg2015malignanthyperthermiaa pages 1-2, frassanito2023realevidenceand pages 1-3).

10. Diagnostics

10.1 Clinical tests / biomarkers

  • Functional contracture testing (gold standard): in vitro contracture testing of biopsied muscle with halothane and caffeine (IVCT/CHCT) remains central (rosenberg2015malignanthyperthermiaa pages 1-2, bin2022malignanthyperthermiaa pages 5-7).
  • Clinical scoring (when definitive tests unavailable): Larach Clinical Grading Scale is referenced as a tool to aid diagnosis when functional/genetic confirmation is not immediately available (bin2022malignanthyperthermiaa pages 5-7).
  • Laboratory: CK elevation and rhabdomyolysis markers (hyperkalemia, myoglobinuria) support diagnosis and severity (rosenberg2015malignanthyperthermiaa pages 1-2).

10.2 Genetic testing approach (current practice)

NGS and gene panels focusing on RYR1, CACNA1S, STAC3 are emphasized as increasingly used in neuromuscular and perioperative risk workups, but negative genetic testing does not exclude susceptibility given heterogeneity and incomplete knowledge (frassanito2023realevidenceand pages 1-3, bin2022malignanthyperthermiaa pages 5-7).

10.3 Diagnostic pathway (visual evidence)

A 2023 pediatric-focused review provides a diagnostic pathway/algorithm figure for investigating MH susceptibility (frassanito2023realevidenceand media 2ab373ad).

10.4 Differential diagnosis

Perioperative hypermetabolic/rhabdomyolysis phenotypes overlap with other syndromes (e.g., anesthesia-induced rhabdomyolysis), creating diagnostic dilemmas noted in perioperative literature (ruta2025perioperativenursingof pages 2-3).

11. Outcome / prognosis

11.1 Mortality and morbidity trends

Mortality has decreased substantially with improved recognition and dantrolene availability: Rosenberg et al. states mortality decreased “from 80% thirty years ago to <5% in 2006” (rosenberg2015malignanthyperthermiaa pages 1-2). Delays in dantrolene and inadequate monitoring are associated with higher complication and mortality risk in modern analyses (rosenberg2015malignanthyperthermiaa pages 2-4, toyota2023rapiddantroleneadministration pages 6-6).

11.2 Prognostic factors (examples)

  • Time to dantrolene and temperature at the time of administration are associated with prognosis in modern observational analyses of severe MH events (toyota2023rapiddantroleneadministration pages 6-6).
  • Adequate core temperature monitoring is associated with reduced risk of death/complications in perioperative MH analyses summarized in authoritative reviews (rosenberg2015malignanthyperthermiaa pages 2-4).

12. Treatment

12.1 Acute pharmacotherapy

  • Dantrolene sodium is the specific antagonist/antidote and should be available wherever general anesthesia is administered (rosenberg2015malignanthyperthermiaa pages 1-2). Early administration is emphasized as life-saving in modern outcome analyses (toyota2023rapiddantroleneadministration pages 6-6).

CHEBI suggestion: dantrolene (CHEBI identifier should be added from CHEBI database in a structured follow-up query; not retrievable from current context).

MAXO suggestions (examples; to be verified/expanded against MAXO): dantrolene administration; trigger agent discontinuation; active cooling; hyperkalemia treatment; intensive care monitoring.

12.2 Supportive care (real-world implementation)

Supportive measures include stopping triggers, ventilating with 100% oxygen, cooling, and correction of metabolic derangements (acidosis/hyperkalemia), with ICU-level monitoring for complications/recurrence (frassanito2023realevidenceand pages 9-10, rosenberg2015malignanthyperthermiaa pages 1-2).

12.3 Anesthesia machine preparation and activated charcoal filters

For patients with known/suspected MHS, trigger-free anesthesia is recommended and workstation preparation is operationally important. A 2023 review specifies: - remove vaporizers; replace breathing circuits and soda lime; flush machine per manufacturer guidance (frassanito2023realevidenceand pages 9-10). - Activated charcoal filters (ACFs): “have been shown to rapidly and cost-efficiently decrease the concentration of anesthetic vapors to <5 ppm in 2–3 min and to maintain this low concentration… for up to 12 h with fresh gas flows of at least 3 L min−1” and should be applied to inspiratory and expiratory limbs; additionally, “the anesthesia machine will still need to be flushed with high fresh gas flows (≥10 L/min) for 90 s before placing the activated charcoal filters” (frassanito2023realevidenceand pages 9-10).

13. Prevention

13.1 Primary prevention (perioperative)

  • Risk identification (family/personal history, congenital myopathy features, prior anesthetic events) and planning trigger-free anesthesia (regional anesthesia or TIVA) with continuous EtCO2 and core temperature monitoring (frassanito2023realevidenceand pages 9-10).
  • System readiness: cognitive aids, MH carts/kits, simulation training, and rapid access to dantrolene (frassanito2023realevidenceand pages 9-10, ruta2025perioperativenursingof pages 2-3).

13.2 Secondary prevention

  • Confirming susceptibility in families: IVCT/CHCT and/or genetic testing in specialized centers to guide future anesthesia planning (bin2022malignanthyperthermiaa pages 5-7, frassanito2023realevidenceand pages 1-3).

14. Other species / natural disease

MH occurs in multiple species: “MH affects humans, certain pig breeds, dogs and horses” (rosenberg2015malignanthyperthermiaa pages 1-2). Inheritance differs: autosomal dominant in humans versus autosomal recessive in pigs (rosenberg2015malignanthyperthermiaa pages 1-2).

15. Model organisms

Multiple models are used to study Ca2+ dysregulation and to test interventions: - Pig models (porcine stress syndrome) as a natural disease model (rosenberg2015malignanthyperthermiaa pages 1-2). - Mouse models with RYR1 variants and Ca2+ dysregulation discussed in major reviews (kan2025researchhotspotsand pages 12-12, rosenberg2015malignanthyperthermiaa pages 12-13).

Recent developments (2023–2024 emphasis) and expert analysis

  1. Operational prevention has become more systematized: 2023 pediatric-focused synthesis emphasizes trigger-free hospitalization, workstation preparation, and activated charcoal filters to rapidly achieve safe low volatile concentrations (frassanito2023realevidenceand pages 9-10, frassanito2023realevidenceand pages 1-3).
  2. Quantitative outcomes research reinforces “time-to-dantrolene” as critical: modern observational analyses (Japan) associate delayed dantrolene and higher temperatures at administration with mortality, reinforcing rapid-response protocols (toyota2023rapiddantroleneadministration pages 6-6).
  3. Diagnostics are shifting toward integrated, less invasive strategies: Reviews highlight the expanding use of NGS, the challenge of RYR1 VUS interpretation, and the need for shared variant databases and functional correlation to avoid unnecessary invasive testing (frassanito2023realevidenceand pages 13-15).

Data gaps relative to the template (not retrievable from current citable context)

  • MONDO ID, Orphanet ID, MeSH, and ICD-10/ICD-11 mappings were not directly retrievable from the current evidence corpus with citable IDs.
  • Detailed allele frequencies (gnomAD) and ClinVar/ClinGen pathogenicity summaries for specific variants were not retrieved in this run.

These elements should be added via targeted queries to OMIM/Orphanet/MONDO/MeSH/ClinVar/gnomAD in a subsequent structured database retrieval step.

References

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  2. (frassanito2023realevidenceand pages 1-3): Luciano Frassanito, Fabio Sbaraglia, Alessandra Piersanti, Francesco Vassalli, Monica Lucente, Nicoletta Filetici, Bruno Antonio Zanfini, Stefano Catarci, and Gaetano Draisci. Real evidence and misconceptions about malignant hyperthermia in children: a narrative review. Journal of Clinical Medicine, 12:3869, Jun 2023. URL: https://doi.org/10.3390/jcm12123869, doi:10.3390/jcm12123869. This article has 20 citations.

  3. (toyota2023rapiddantroleneadministration pages 6-6): Yukari Toyota, Takashi Kondo, Daiki Shorin, Ayako Sumii, Kenshiro Kido, Tomoyuki Watanabe, Sachiko Otsuki, Rieko Kanzaki, Hirotsugu Miyoshi, Toshimichi Yasuda, Yousuke T. Horikawa, Keiko Mukaida, and Yasuo M. Tsutsumi. Rapid dantrolene administration with body temperature monitoring is associated with decreased mortality in japanese malignant hyperthermia events. BioMed Research International, Feb 2023. URL: https://doi.org/10.1155/2023/8340209, doi:10.1155/2023/8340209. This article has 12 citations.

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  5. (biesecker2020genomicscreeningfor pages 1-2): Leslie G. Biesecker, Robert T. Dirksen, Thierry Girard, Philip M. Hopkins, Sheila Riazi, Henry Rosenberg, Kathryn Stowell, and James Weber. Genomic screening for malignant hyperthermia susceptibility. Anesthesiology, 133:1277-1282, Sep 2020. URL: https://doi.org/10.1097/aln.0000000000003547, doi:10.1097/aln.0000000000003547. This article has 40 citations and is from a domain leading peer-reviewed journal.

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  13. (ruta2025perioperativenursingof pages 2-3): Federico Ruta, Annalisa Della Monica, Francesca Dal Mas, Tatiana Bolgeo, Ippolito Notarnicola, Cataldo Procacci, Paolo Ferrara, Alice Masini, Stefano Mancin, Giovanni Cangelosi, Mauro Parozzi, and Francesco Sacchini. Peri-operative nursing of patients with malignant hyperthermia: a narrative literature review. Surgeries, 6:78, Sep 2025. URL: https://doi.org/10.3390/surgeries6030078, doi:10.3390/surgeries6030078. This article has 0 citations.

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  16. (frassanito2023realevidenceand media 2ab373ad): Luciano Frassanito, Fabio Sbaraglia, Alessandra Piersanti, Francesco Vassalli, Monica Lucente, Nicoletta Filetici, Bruno Antonio Zanfini, Stefano Catarci, and Gaetano Draisci. Real evidence and misconceptions about malignant hyperthermia in children: a narrative review. Journal of Clinical Medicine, 12:3869, Jun 2023. URL: https://doi.org/10.3390/jcm12123869, doi:10.3390/jcm12123869. This article has 20 citations.

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