Valerie Neff Newitt
October 2026—The Food and Drug Administration issued an alert in July about its investigation into the safety of sevoflurane and other general anesthetics in adult and pediatric patients of maternal Venezuelan ancestry, based on published scientific reports of unexpected catastrophic outcomes.
The American Society of Anesthesiologists and the Society for Pediatric Anesthesia had issued a joint communication months earlier. Almost all of the affected patients are reported to have received sevoflurane.
Genetic testing performed on a subset of patients revealed multiple mitochondrial mutations. A point mutation of the NADH dehydrogenase 4 (ND4) gene (MT-ND4 m.11232T>C), a subunit of complex I of the mitochondrial electron transport chain, was reported to be the best described. The ASA and SPA said complex I is a known target of volatile anesthetics and known also to be inhibited by propofol. Prior work found that impaired complex I activity correlates with hypersensitivity to volatile anesthetics, the organizations said.
The ClinGen mitochondrial disease variant curation expert panel on April 16 approved the classification of MT-ND4 m.11232T>C as likely pathogenic for volatile anesthetic hypersensitivity inherited in a mitochondrial manner.
“The genetic and functional evidence supporting a pathogenic role for this variant emerged very recently,” says Ryan J. Schmidt, MD, PhD, assistant director of the clinical genomics laboratory, Center for Personalized Medicine, Department of Pathology and Laboratory Medicine, Children’s Hospital Los Angeles, and assistant professor of clinical pathology, Keck School of Medicine of USC. He is a member of the CAP/ACMG Biochemical and Molecular Genetics Committee.
The expert panel’s review and classification “provides a definitive interpretation based on the information that is currently available for this variant,” Dr. Schmidt says. The panel members said 11 cases had been reported by that date in unrelated individuals who experienced volatile anesthetic hypersensitivity, many of whom were of Venezuelan origin and haplogroup D1b.
The speed with which the report in the medical literature translated into an advisory from the medical societies was unusual, but the variant is likely to lead to sevoflurane hypersensitivity and should be considered clinically actionable, Dr. Schmidt says.
“They wanted to get in front of it because the outcomes can be severe,” he says of the advisory.
The variant identified is in the mitochondrial DNA, a small circular DNA that lives outside the nucleus and is maternally inherited, he notes. Heteroplasmy means some, not all, of the mitochondrial DNA sequences have a mutation. “It’s only affecting, say, 50 percent or 30 percent of your mitochondrial DNA sequences,” for example. The expert panel reported that the variant was present at homoplasmy in the affected individuals. “In the homoplasmic case, it’s affecting 100 percent,” Dr. Schmidt says, so all of the mitochondrial DNA molecules have the variant of interest.
The Canadian Anesthesiologists’ Society said in its March advisory statement that not all individuals with MT-ND4 m.11232T>C have experienced adverse outcomes after exposure to general anesthesia. “The precise pathophysiologic mechanism and magnitude of risk remain under investigation,” it said. “Therefore, a negative family history of complications after inhaled anesthetics does not rule out carrying the variant of concern.”
At Children’s Hospital Los Angeles, testing for the variant has been ordered preoperatively for patients with a maternal history of Venezuelan ancestry, since the time of the joint ASA/SPA communication and at the direction of the hospital’s anesthesiologists and medical geneticists.
“The testing was already available through a custom-focused exome test that includes mitochondrial DNA capture,” Dr. Schmidt says. Institutionwide genetic counselors who work closely with the laboratory advise providers on test selection.
The laboratory offers targeted testing by Sanger sequencing as well as whole genome or the custom-focused exome testing. “NGS-based testing offers the advantage of increased analytical sensitivity, but targeted Sanger sequencing may be useful for this variant,” Dr. Schmidt says, because of the homoplasmy reported to date. “Ideally, a positive control sample is available when performing targeted Sanger sequencing to guard against allele dropout,” he says, so the latter method is often chosen for familial follow-up testing.
For laboratories that perform high-complexity molecular diagnostic testing, “testing for the m.11232T>C variant should be fairly straightforward.” When there is a clinically urgent need, his laboratory can complete the testing in less than two weeks. All such tests at Children’s Hospital Los Angeles have had negative results thus far.
Authors of a study published this year (Sanz-Pons J, et al. Anesthesiology. 2026;144[6]:1286–1298) reported on the clinical and genetic studies, among others, performed on seven patients who experienced severe acute neurologic deterioration after the administration of general anesthetics during predominantly minor surgical procedures. 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.
The authors write, “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.” Propofol did not elicit a differential effect in cells harboring this variant.
Most of the patients included in this study presented with no significant underlying health conditions.
In its July alert, the FDA wrote that although the currently reported cases have been linked to sevoflurane, “this genetic variant raises concerns regarding all volatile anesthetics.”
Laboratories should be aware of the relationship of this variant with hypersensitivity to certain anesthetics and, if appropriate, given the demands of their institution, consider offering testing for this variant, Dr. Schmidt says.
“Further evidence may emerge that allows for more definitive classification of this variant,” he says, and the risks associated with the use of specific anesthetic agents may also become clearer.
“Our understanding of the function of genes and their connection with disease is growing every day,” he adds, and the information and precautions related to m.11232T>C are “part of a broader trend of the increased use of genetic testing across all specialties of medicine.”
Valerie Neff Newitt is a writer in Audubon, Pa.