Effects of a mitochondrial genetic variant on sevoflurane hypersensitivity

Background: Recently, various anesthesiology societies have reported cases involving pediatric patients of Venezuelan origin who underwent surgery under general anesthesia and subsequently developed serious neurological impairment or died. However, the cause of this condition was unknown. Methods: Clinical and genetic studies were conducted on seven patients who experienced severe acute neurologic deterioration following the administration of general anesthetics during predominantly minor surgical procedures. Genetic-molecular, biochemical, and cellular studies were also performed on fibroblasts and cybrids treated with general anesthetics. Results: In our cohort, acute perioperative events were observed in temporal association with anesthetic exposure. No adverse events were observed in a subset of the same individuals when only intravenous anesthesia was used. All patients shared a mitochondrial DNA haplotype that includes the m.11232T>C genetic variant, which results in the substitution of proline for leucine at position 158 (L158P) of the ND4 subunit of respiratory complex I in the electron transport chain. In vitro studies showed that sevoflurane exposure in cells carrying this genetic variant induces a pronounced suppression of mitochondrial oxygen consumption, with prominent effects on complex I–dependent respiratory pathways. In contrast, propofol did not elicit a differential effect in cells harboring this genetic variant. Conclusions: These findings suggest that individuals carrying the m.11232T>C mitochondrial DNA variant may be at increased risk of severe neurologic deterioration following exposure to anesthetic agents. Further studies are needed to define the underlying mechanisms and to determine anesthetics-specific risks. These results have important implications for improving the safety of surgical interventions and open new avenues in the field of mitochondrial pharmacogenetics of general anesthesia.