ND4 variant: the anaesthetist and the history

September 21, 2026 · Read 7 min

In a previously healthy patient of Venezuelan maternal lineage (mother or maternal grandmother), basal ganglia injury, severe neurological deterioration, or death may follow routine general anaesthesia with a volatile agent, with no intraoperative incident and no hypermetabolic component. There is currently no point-of-care screening test and no preceding phenotype to identify the patient at risk, and the genetic report, when it arrives, classifies the same variant in two opposite ways.

1. The reported presentation

Three features make it recognisable:

• No intraoperative warning. In the reported cases the anaesthetic proceeded without incident.
• Independent of the magnitude of surgery. The published cases followed routine, short procedures, so nothing reported confines the risk to minor surgery.
• Exposure to a volatile agent. Present in most reported cases, with sevoflurane the most frequent agent.

2. Screening in the preoperative clinic

Two questions, asked with the reason explained:

• Where the mother was born.
• Where the maternal grandmother was born.

The paternal line does not transmit and is not asked about. The mother of unknown origin and the patient conceived by oocyte donation are both included.

Three events in the family history after general anaesthesia strengthen the suspicion:

• Prolonged emergence.
• Neurological deterioration or stroke.
• Unexpected perioperative death.

Their absence does not rule out a carrier: there are carrier mothers with no symptoms and no anaesthetic history of their own.

3. Reading the genetic report

Each classification corresponds to a different condition evaluated, and that information does not always appear in the report.

What to request from the laboratory

Three elements go in the request:

• A specific search for m.11232T>C, also written p.Leu158Pro.
• An explicit report of presence or absence.
• Which condition the finding was classified against.

The sample type, blood or buccal swab, is defined by the laboratory; the variant is detectable in blood. The test requires specific informed consent and genetic counselling, which extends to relatives along the maternal line.

4. Management with no result available

The decision is stratified by urgency:

• Elective procedure with laboratory access. It is postponed until the result is available.
• Urgent case, or no access to testing. The lowest-risk plan is used and the test is offered afterwards.

Individual sensitivity is not known before induction: with complex I deficiency (NADH dehydrogenase, the first enzyme of the respiratory chain) the sevoflurane concentration required falls to less than half.

Reference multimodal regimen

The ranges below are illustrative examples from contemporary adult anaesthetic practice and are not dosing recommendations specific to this variant. For 16 years and above, to ideal body weight:

• Propofol 50-125 mcg/kg/min.
• Dexmedetomidine 0.2-0.7 mcg/kg/h.
• Ketamine 0.2-0.5 mg/kg/h.
• Remifentanil 0.05-0.15 mcg/kg/min.
• Lidocaine 1-1.5 mg/kg/h.

Where a regional technique predominates, sedation falls to propofol 25-75 mcg/kg/min and dexmedetomidine 0.2-0.5 mcg/kg/h. Below 16 years there are no transferable ranges: management is individualised with paediatric anaesthesia.

Intraoperative targets

• Blood glucose 110-180 mg/dL, with a shortened fast.
• Avoid sustained mean arterial pressure < 65 mmHg in adults; vasopressor therapy is not withheld where indicated.
• Temperature 36-37 °C, normoxia and normocapnia, avoiding prolonged FiO2 > 0.80.
• pH ≥ 7.30.
• Processed EEG from induction, without burst suppression.
• Lactate by trend: up to 2 mmol/L is the physiological range; 2-3 mmol/L marks mild metabolic stress; 3-4 mmol/L warrants evaluation of tissue perfusion and oxygen delivery; sustained above 4 mmol/L, clinically significant metabolic stress.

The level of care available at the centre does not change management. For straightforward procedures, the absence of a paediatric intensive care unit is not in itself a criterion for referral, and the planned pathway of day surgery, admission, or intensive care is maintained.

5. Postoperative surveillance and the limits of provisional guidance

The reported postoperative pattern:

• Delayed emergence that does not resolve, seizures, or focal deficit.
• Progression between 24 and 72 h.
• No hypermetabolic picture. There is no established link between mitochondrial myopathy and malignant hyperthermia susceptibility.

Before the pattern is attributed to the variant, the common causes are excluded, among them residual neuromuscular block and hypoglycaemia. Recovery to baseline is confirmed in level of consciousness, speech, and motor power, and the absence of focal signs is documented, with serial neurological assessment in the early postoperative period. Any abnormality activates the local protocols for urgent neurological care, with neuroimaging and metabolic monitoring.

Notification to the pharmacovigilance service of the centre and to the national registries is part of management.

The recommendations are provisional and the professional societies are updating them. Their scope has extended to prolonged sedation with volatile agents outside theatre. The current version of the society document that corresponds to local practice is checked before any of the above is applied.