Authors: Sanz-Pons J et al.
Anesthesiology, March 9, 2026, 10.1097/ALN.0000000000006029
This study investigated a possible genetic explanation for a series of severe neurologic complications observed in pediatric patients of Venezuelan origin following general anesthesia. Several anesthesiology societies had previously reported unexplained cases in which children undergoing relatively minor procedures developed acute neurological deterioration or death after exposure to general anesthetics. The authors sought to determine whether a mitochondrial genetic variant could explain this apparent hypersensitivity.
The investigators conducted clinical, genetic, biochemical, and cellular analyses in seven affected patients who experienced severe neurologic deterioration temporally associated with anesthetic exposure. These patients underwent predominantly minor surgical procedures but developed serious perioperative neurologic events shortly after anesthesia. Importantly, in a subset of these patients, no adverse events occurred when only intravenous anesthesia was used in subsequent procedures.
Genetic analysis revealed that all affected patients shared a specific mitochondrial DNA haplotype containing the m.11232T>C mutation. This mutation produces a substitution of proline for leucine at position 158 of the ND4 subunit of mitochondrial respiratory chain complex I. Because complex I plays a central role in oxidative phosphorylation and cellular energy production, disruption of its function could potentially produce profound metabolic consequences in vulnerable tissues such as the brain.
To explore the functional implications of this variant, the investigators performed in vitro experiments using patient-derived fibroblasts and cybrid cellular models carrying the mutation. When exposed to sevoflurane, cells containing the m.11232T>C variant showed significant suppression of mitochondrial oxygen consumption. This effect appeared particularly pronounced in pathways dependent on complex I activity within the electron transport chain.
In contrast, exposure to propofol did not produce the same differential mitochondrial dysfunction in cells carrying the mutation. This observation aligns with the clinical finding that intravenous anesthesia was tolerated in some affected individuals, suggesting that susceptibility may be agent-specific rather than a general anesthetic sensitivity.
The findings support the hypothesis that certain mitochondrial genetic variants may predispose patients to severe neurologic complications after exposure to specific anesthetic agents. The authors propose that sevoflurane may interact with mitochondrial respiratory function in susceptible individuals, producing acute energy failure in neural tissue.
Although the study involves a small number of patients, it provides a plausible mechanistic explanation linking anesthetic exposure to mitochondrial dysfunction in genetically susceptible individuals. The work also highlights a broader concept: pharmacogenetic variability in anesthetic responses may extend beyond traditional nuclear gene polymorphisms to include mitochondrial DNA variants.
The authors conclude that further investigation is necessary to determine the prevalence of this mutation, identify additional susceptible populations, and better understand anesthetic-specific risks in mitochondrial disorders. If confirmed, these findings could eventually inform personalized anesthetic strategies for patients with certain mitochondrial genetic backgrounds.
What You Should Know
This study addresses a concerning cluster of unexplained neurologic complications reported in pediatric patients following general anesthesia.
All affected patients shared a mitochondrial DNA mutation affecting complex I of the electron transport chain.
Laboratory studies showed that sevoflurane markedly impaired mitochondrial respiration in cells carrying the mutation.
Propofol did not produce the same effect, suggesting anesthetic-specific vulnerability.
The findings introduce the concept of mitochondrial pharmacogenetics in anesthesiology, where certain genetic variants may influence anesthetic safety.
Key Points
Seven patients with severe neurologic deterioration after anesthesia shared the mitochondrial m.11232T>C variant.
The mutation affects the ND4 subunit of mitochondrial respiratory chain complex I.
Sevoflurane exposure significantly suppressed mitochondrial oxygen consumption in cells carrying the variant.
Propofol did not show the same mitochondrial impairment.
The results suggest a potential genetic susceptibility to anesthetic-related neurologic injury.
Further research is required to determine the clinical prevalence and implications of this mitochondrial variant.
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