Authors: Yanez Hinojosa C I et al.
Anesthesiology, February 18, 2026.
Potential Mitochondrial Pharmacogenetic Susceptibility to Severe Neurologic Events after General Anesthesia: Report from the Chilean Ministry of Health.
This report describes a cluster of severe neurologic complications that occurred after general anesthesia in previously healthy patients in Chile. The cases prompted a national investigation and raised the possibility that a mitochondrial pharmacogenetic susceptibility may contribute to rare but severe neurologic injury after anesthesia.
In July 2025, the Chilean Society of Anesthesiology reported five pediatric patients who developed severe neurologic injury following elective surgery performed between 2021 and 2025. Four of these children later died. All affected children had mothers of Venezuelan descent.
Following this report, the Chilean Ministry of Health implemented a national surveillance initiative requesting reports of any cases since 2021 involving neurologic injury or death after general anesthesia. Within one week, two additional cases were identified, including one adult patient.
The initial case series therefore included seven patients—six children and one adult—with a median age of five years. Five of the seven patients were male. Most patients had no prior neurologic history and minimal comorbidities.
The procedures performed before the neurologic events were relatively minor and included:
• Dermal graft surgery
• Flexor tendon repair
• Video-assisted thoracoscopic surgery
• Adenotonsillectomy
• Dental restoration
• Two inguinal hernia repairs
All patients received sevoflurane anesthesia. Six of the seven patients also received propofol, and all received fentanyl.
Neurologic symptoms developed either immediately after anesthesia emergence or within 10 days following surgery. Clinical manifestations included delayed awakening, altered consciousness ranging from drowsiness to coma, abnormal limb movements, cranial nerve deficits, extrapyramidal symptoms, and corticospinal tract dysfunction.
Four patients developed severe cerebral edema with intracranial hypertension and ultimately died. The median time from symptom onset to death was approximately 9.5 days. The remaining three patients survived but developed significant neurologic sequelae.
Neuroimaging findings commonly demonstrated bilateral basal ganglia injury with additional involvement of deep gray matter structures such as the cerebellum and substantia nigra. These findings resembled hypoxic–ischemic encephalopathy.
Extensive investigations were performed to determine the cause of these events. Clinical audits found no evidence of anesthesia equipment malfunction, medication errors, or deviations from standard protocols. In one case, malignant hyperthermia was initially suspected but genetic testing for common malignant hyperthermia genes (RYR1, CACNA1S, and STAC3) was negative.
Because mitochondrial dysfunction was suspected, genetic testing was performed in several patients. Whole-exome sequencing did not identify causative variants. However, mitochondrial DNA sequencing identified a homoplasmic variant in the MT-ND4 gene (m.11232T>C, p.Leu158Pro) in three cases.
The MT-ND4 gene encodes a subunit of mitochondrial complex I involved in oxidative phosphorylation and cellular energy production. Previous experimental studies have demonstrated that volatile anesthetics such as sevoflurane and isoflurane can inhibit mitochondrial complex I activity, reducing ATP production and increasing reactive oxygen species generation.
In individuals with underlying mitochondrial dysfunction, such inhibition could theoretically worsen metabolic stress and lead to neuronal injury. Although the MT-ND4 variant identified in these patients has previously been associated with chronic progressive external ophthalmoplegia, it has not previously been linked to acute peri-anesthetic encephalopathy.
Because the genetic variant is currently classified as a variant of uncertain significance, a direct causal relationship between anesthesia exposure and neurologic injury cannot yet be confirmed. However, the clustering of cases and shared genetic findings suggest a potential pharmacogenetic susceptibility.
In response to these findings, the Chilean Ministry of Health issued guidance recommending heightened vigilance during preoperative assessment, particularly when mitochondrial disorders are suspected. The guidance also suggests considering anesthetic techniques that minimize mitochondrial metabolic stress when such risk is identified.
National surveillance, epidemiologic studies, and genetic research are currently underway to better understand the potential relationship between mitochondrial variants and perioperative neurologic injury.
Key Points
• Seven patients in Chile developed severe neurologic injury after general anesthesia between 2021 and 2025.
• Six were children and four patients died.
• All patients received sevoflurane, and most also received propofol and fentanyl.
• Neuroimaging often showed bilateral basal ganglia and deep gray matter injury consistent with hypoxic–ischemic encephalopathy.
• Genetic testing identified a mitochondrial DNA variant in the MT-ND4 gene in several patients.
• Volatile anesthetics may impair mitochondrial complex I function, potentially worsening underlying mitochondrial dysfunction.
• A causal relationship has not been established, but the cases raise concern for possible mitochondrial pharmacogenetic susceptibility.
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