MT-ND4 m.11232T>C in Venezuelan Maternal Lineage: An Anesthesia Management Protocol

The 30-Second Summary

A homoplasmic mitochondrial DNA point mutation — m.11232T>C in the MT-ND4 gene — has been identified in a growing series of previously healthy adult and pediatric patients of Venezuelan maternal ancestry who suffered catastrophic neurologic injury (predominantly bilateral basal ganglia infarcts) and, in some cases, death after routine general anesthesia. As of April 2026, approximately forty cases have been reported across the United States, Chile, Spain, Germany, and Guyana. Most identified families trace back to Indigenous American maternal lineages from Carabobo, Venezuela, although the variant has also been documented in patients without a known Carabobo connection. Joint statements have been issued by the ASA/SPA (January 27, 2026) and the ESAIC/ESPA/EURO-NMD/E-MIT consortium in early 2026.

The clinical fingerprint is consistent: an otherwise healthy patient, a routine elective case, a sevoflurane-based anesthetic, and an unexplained postoperative neurologic event. The pre-anesthetic workup is unremarkable. The mutation is silent until the triggering anesthetic. By the time the diagnosis is made, the injury is done.

The intraoperative recommendation is short and actionable: avoid volatile anesthetics, run a TIVA-based or regional plan, use processed EEG to avoid burst suppression, and consider cerebral oximetry. The harder problem is the preoperative one: identifying the at-risk patient weeks before the case so the plan can actually be assembled.

What the Mutation Does

MT-ND4 encodes a subunit of mitochondrial respiratory chain complex I(NADH:ubiquinone oxidoreductase) — the first and largest enzyme in oxidative phosphorylation. The m.11232T>C variant produces a leucine-to-proline substitution at position 158 of the ND4 subunit. In cultured cells carrying the homoplasmic variant, sevoflurane exposure produced significant suppression of mitochondrial oxygen consumption, with effects especially pronounced in complex I–dependent pathways. Propofol did not reproduce this effect to the same degree in those models, suggesting agent-specific vulnerability rather than a generalized anesthetic intolerance.

Clinically, volatile anesthetics are well-described inhibitors of complex I. In a patient with normal mitochondrial reserve this inhibition is well-tolerated. In a patient whose complex I is already structurally compromised, the additional pharmacologic hit can push energy-dependent neurons — particularly in the basal ganglia, which have an exceptionally high metabolic rate and limited tolerance for ATP shortfall — past the point of recovery. The radiographic result is bilateral basal ganglia infarction, with or without diffuse cerebral edema.

Because mitochondrial DNA is inherited exclusively from the mother, a homoplasmic mtDNA variant is passed intact down the maternal line. The patient's ethnicity, paternal ancestry, and self-identification are irrelevant to risk. What matters is whether the patient's mother — and her mother — carried the variant.

The Preoperative Screen

The ASA/SPA joint communication recommends asking every preoperative patient about maternal Venezuelan heritage. It also explicitly cautions that a negative family history of anesthetic complications does not rule out the risk — most affected patients were asymptomatic with unremarkable family histories before their triggering exposure. Two screening questions cover the relevant territory:

1. “Was your mother — or her mother — born in Venezuela, or of Venezuelan descent (particularly the Carabobo region)?”

2. “Has your mother, or any blood relative on your mother's side, ever had an unexplained complication after surgery or anesthesia — a stroke, a coma, a death that nobody could explain?”

A positive answer to either question should flag the chart for the anesthesia team. The Carabobo qualifier is sensitivity-boosting, not specificity-defining — broader Venezuelan maternal ancestry is sufficient to warrant the modified plan, since the variant has been documented outside Carabobo as well.

Confirmatory genetic testing is available — CHOP's Division of Genomic Diagnostics, GeneDx, and Baylor Genetics all offer targeted m.11232T>C analysis or full mtDNA sequencing (costs range from approximately $250 for the known-variant panel to $3,000 for full sequencing). For an elective case with enough lead time, this is the highest-confidence pathway. For most real-world elective surgical scheduling, however, the practical recommendation from the joint statements is to treat the patient as potentially at-risk and modify the anesthetic plan accordingly rather than to delay surgery awaiting confirmatory testing.

Intraoperative Management

Anesthetic technique

• Total intravenous anesthesia (TIVA) is the technique of choice per the ESAIC/ESPA/EURO-NMD/E-MIT joint statement. Regional anesthesia (spinal, epidural, peripheral nerve blocks) is preferred where the procedure allows.
• Avoid all volatile anesthetics until further data is available — sevoflurane has been involved in the majority of reported cases, but isoflurane and desflurane are also complex I inhibitors and should be considered presumptively unsafe in this population.
• Propofol may be used cautiously — at the lowest effective dose, for the shortest possible duration, with adjuvants (dexmedetomidine, opioids, ketamine) to reduce overall propofol exposure. Several case reports document uneventful propofol-based anesthetics in confirmed carriers; the published guidance does not classify propofol as a hard contraindication.
• Nitrous oxide is not explicitly addressed in the current joint statements. Given its known effects on B12 metabolism and methionine synthase activity in the broader mitochondrial-disease literature, a cautious approach is reasonable until specific data exists.
• Agents not currently implicated include midazolam, dexmedetomidine, ketamine, and short-acting opioids (fentanyl, remifentanil, sufentanil). No data has been reported yet for remimazolam in this population.

Monitoring

• Processed EEG (BIS or equivalent) is advisable — the ASA/SPA communication specifically recommends processed EEG to avoid burst suppression. Deeper- than-necessary anesthesia adds pharmacologic insult to a mitochondrion that cannot afford it. Target the lightest depth consistent with the procedure.
• Near-infrared spectroscopy (NIRS) for cerebral oxygenation monitoring is reasonable in known or suspected carriers, particularly for cases longer than 60 minutes or with anticipated hemodynamic variability.
• Serial blood lactate is mentioned in the European joint statement as a potential adjunct, with the explicit caveat that its predictive utility in this specific pathology is unknown. Treat it as supportive rather than diagnostic.
• Standard ASA monitoring (ECG, NIBP/A-line as indicated, capnography, pulse oximetry, temperature) — but with a lower threshold for invasive arterial monitoring in longer cases so that real-time blood gas, glucose, and lactate sampling is straightforward.

Physiologic targets

Patients with mitochondrial dysfunction tolerate physiologic stress poorly. The general mitochondrial-disease anesthesia literature applies here even though it predates the m.11232T>C variant specifically:

• Maintain normothermia. Both hypothermia and hyperthermia increase oxidative stress and mitochondrial demand.
• Avoid hypoglycemia. Minimize the preoperative fast and consider dextrose-containing maintenance fluid for longer cases or pediatric patients.
• Avoid lactated Ringer's if possible. Patients with impaired oxidative phosphorylation already accumulate lactate; exogenous lactate load is counterproductive. Plasma-Lyte, Normosol, or normal saline are preferable.
• Maintain normocarbia and normotension. Hyperventilation and induced hypotension both reduce cerebral perfusion in a brain that has narrower margins than average.
• Avoid prolonged tourniquet use where avoidable, and consider lactate trending after prolonged tourniquet release.

Neuromuscular blockade

Not specifically addressed in the joint statements. The general principle from the mitochondrial anesthesia literature — that non-depolarizing agents may have prolonged effect in mitochondrial-disease patients — argues for quantitative train-of-four monitoring and titrated dosing. Sugammadex is a reasonable reversal agent. Succinylcholine is not contraindicated by the variant itself (this is not malignant hyperthermia), but the broader cautions around succinylcholine in any patient with subclinical neuromuscular disease still apply.

Postoperative period

Extended PACU observation with a low threshold for neurologic assessment is appropriate for the first identified case in any practice. Reported events have predominantly emerged in the immediate postoperative period — failure to wake appropriately, new focal deficit, unexplained altered mental status. Any of these in a known or suspected carrier warrants urgent neuroimaging (MRI with DWI is the highest-yield study for basal ganglia infarction) and neurology consultation.

A One-Page Intraop Checklist

Where MyPreOp.ai Fits

The hardest part of this is not the intraop plan. The intraop plan is straightforward — every modern anesthesia practice can deliver a TIVA-with-processed-EEG anesthetic without difficulty. The hard part is knowing in advance which patient needs it.

Pre-op clearance in private practice is built around the surgeon's office workflow. Coordinators collect history, request consults, upload records. The anesthesia provider often does not see the chart until 24–48 hours before the case. If the maternal-ancestry question wasn't asked at the surgeon's intake — and most paper intake forms do not ask it — the anesthesia team learns about the risk on the morning of surgery, at which point the options are to cancel or to proceed with whatever plan was already prepared.

MyPreOp.ai screens for this risk at the front of the workflow. Every patient intake asks the maternal heritage question — including the Carabobo, Venezuela qualifier — and asks whether the patient's mother (or any maternal blood relative) has ever had an unexplained complication after surgery or anesthesia. A positive answer triggers an explicit flag in the clearance report, with the relevant ASA / APSF / SPA / ESAIC references attached, so the anesthesia provider has the heads-up weeks before the case — not minutes before induction.

This is the kind of finding systematic intake catches reliably and paper-based intake misses. It's also the kind of finding that, when missed, ends up in a published case report or a morbidity-and-mortality review. The screening question is free. The intraop modification is standard care. The only thing missing in most practices today is the workflow that connects them.

References

Society guidance:

• American Society of Anesthesiologists. Rare Gene Mutation in Some with Venezuelan Ancestry Linked to Severe Neurologic Complications and Death After General Anesthesia. News release, January 2026. asahq.org
• American Society of Anesthesiologists & Society for Pediatric Anesthesia. Update Regarding Severe Neurological Complications and Death After General Anesthesia in Adult and Pediatric Patients of Venezuelan Ancestry. Joint communication, January 27, 2026. pedsanesthesia.org
• Anesthesia Patient Safety Foundation. Perioperative Practices for Patients of Venezuelan Ancestry. apsf.org
• European Society of Anaesthesiology and Intensive Care, European Society of Paediatric Anaesthesia, ERN EURO-NMD Mitochondrial Working Group, and E-MIT Society. Joint Statement on Anaesthesia-Related Mitochondrial Pharmacogenetic Risk in Individuals with Venezuelan Maternal Ancestry, 2026. esaic.org
• MSeqDR Consortium. m.11232T>C Joint Communication and Anesthesia/Genetic Testing Recommendation Guidelines (Version 1, February 27, 2026). mseqdr.org/T11232C

Case reports and trade press:

• Case report of acute encephalopathy associated with general anesthesia and the m.11232T>C MT-ND4 variant in an adult patient. Revista Española de Anestesiología y Reanimación, March 2026.
• Case series describing severe neurologic complications after sevoflurane in patients with Venezuelan maternal ancestry. Chilean Journal of Anesthesiology (Revista Chilena de Anestesia), March 2026.
• Mitochondrial Genetic Susceptibility to Anesthetic Neurotoxicity in Venezuelan Pediatric Patients. Clinical Surgery Journal
• Anesthesia-Related Neurologic Risk in Patients of Venezuelan Descent: Implications for Ophthalmology. American Journal of Ophthalmology
• Anesthetic Risk Linked to Venezuelan Maternal Lineage. Medscape
• Litman R. New Evidence Alert: Mitochondrial-Linked Hypersensitivity to Volatile Anesthetics. Substack