## Pathophysiology of Malignant Hyperthermia **Key Point:** Malignant hyperthermia (MH) is a pharmacogenetic disorder characterized by abnormal intracellular calcium handling in skeletal muscle. ### Genetic Basis The primary defect involves mutations in genes encoding calcium-handling proteins: - **RYR1 gene** (ryanodine receptor 1) — accounts for ~70% of MH cases - **CACNA1S gene** (L-type calcium channel α1-subunit) — accounts for ~20% of cases ### Mechanism 1. Triggering agents (volatile anesthetics, succinylcholine) cause abnormal activation of the ryanodine receptor 2. Uncontrolled calcium release from the sarcoplasmic reticulum into the cytoplasm 3. Sustained muscle contraction (rigidity) and hypermetabolism 4. Heat generation, rhabdomyolysis, and systemic complications **High-Yield:** The defect is in the calcium release channel itself, NOT in calcium reuptake or mitochondrial function. ### Clinical Manifestation Timeline - Early signs: muscle rigidity, masseter muscle spasm, increased ETCO₂ - Late signs: hyperthermia (often a late sign, not early), rhabdomyolysis, hyperkalemia, myoglobinuria **Clinical Pearl:** Hyperthermia is a late and unreliable sign — early recognition depends on muscle rigidity and increased ETCO₂, not temperature. [cite:Miller's Anesthesia 8e Ch 40]
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