Methylenetetrahydrofolate reductase (MTHFR) deficiency is a rare inherited disorder that interferes with the metabolism of folate and the regulation of homocysteine, an amino acid found in the blood. Typically, the MTHFR enzyme helps convert homocysteine to methionine, which is essential for protein production and many chemical reactions in the body. When this process is impaired, however, homocysteine levels rise, leading to a condition called hyperhomocysteinemia. High homocysteine levels have been linked to vascular damage, clot formation, and neurological problems. The implications and symptoms of MTHFR deficiency are especially important in anesthesia because medications and the stress of surgery can worsen metabolic imbalances and increase the likelihood of complications (1).

Nitrous oxide poses the greatest risk to patients with MTHFR deficiency. This gas inactivates methionine synthase, another enzyme needed to process homocysteine. In healthy patients, this usually causes only a modest increase in homocysteine; however, in patients with MTHFR deficiency, this increase can be significant and harmful, resulting in serious implications for anesthesia. Case reports describe seizures, postoperative regression in children, subacute spinal cord injury, and thrombotic events, such as deep vein thrombosis, pulmonary embolism, and cerebral venous thrombosis, following nitrous oxide exposure (2). Due to these consistent findings, nitrous oxide should be strictly avoided in patients with MTHFR deficiency.

To mitigate the risks of MTHFR deficiency, careful planning is required for other aspects of anesthetic care. Surgical stress, hypoxia, and certain anesthetic agents can exacerbate metabolic instability in these patients. Preoperative optimization is often recommended and includes supplementation with folic acid, vitamin B12, and betaine. These nutrients lower homocysteine levels and support folate-dependent pathways disrupted by MTHFR deficiency, thereby making metabolism more resilient during surgery. In published reports, patients who received this type of support generally experienced smoother perioperative courses and fewer complications (3). During surgery, anesthetic drug choices should be tailored to the individual patient, and regional techniques, such as spinal or epidural anesthesia, may be considered when safe and appropriate.

The implications of MTHFR deficiency in children make them especially vulnerable during anesthesia. Severe cases are often accompanied by seizures, developmental delay, or low muscle tone, which complicate airway management and anesthetic selection. Even relatively minor procedures may carry a heightened risk. Reports describe developmental regression and worsening seizure activity in this group following exposure to anesthesia. The strongest recommendations are to avoid nitrous oxide, consider preoperative vitamin therapy, and involve a multidisciplinary team, including anesthesiologists, pediatricians, and metabolic specialists, to ensure safe care (4).

Although no large-scale clinical trials have been conducted, the available case literature is remarkably consistent. Providing safe anesthesia to patients with MTHFR deficiency requires early recognition of the condition, correction of elevated homocysteine levels through vitamin therapy, and avoidance of drugs that disrupt folate metabolism. When these steps are taken, patients can undergo complex procedures without experiencing major complications (5).

In summary, MTHFR deficiency is rare but nonetheless important for anesthesiologists to understand. The disorder predisposes patients to neurological injury and clotting events, risks that are greatly amplified by nitrous oxide and perioperative stress. Management strategies such as preoperative vitamin supplementation and careful drug selection have been shown to reduce complications. Until larger studies are available, consistent lessons from published cases provide strong guidance: safe outcomes depend on vigilance and tailored anesthetic planning.

References

1. Gerges FJ, Dalal AR, Robelen GT, Cooper B, Bayer LA. Anesthesia for cesarean section in a patient with placenta previa and methylenetetrahydrofolate reductase deficiency. J Clin Anesth. 2006;18(6):455-459. doi:10.1016/j.jclinane.2006.01.006
2. Shay H, Frumento RJ, Bastien A. General anesthesia and methylenetetrahydrofolate reductase deficiency. J Anesth. 2007;21(4):493-496. doi:10.1007/s00540-007-0544-8
3. Cascella M, Arcamone M, Morelli E, et al. Multidisciplinary approach and anesthetic management of a surgical cancer patient with methylene tetrahydrofolate reductase deficiency: a case report and review of the literature. J Med Case Rep. 2015;9:175. Published 2015 Aug 20. doi:10.1186/s13256-015-0662-0
4. Orhon ZN, Koltka EN, Tüfekçi S, et al. Methylene Tetrahydrofolate Reductase Deficiency: the Hidden Risk in Paediatric Anaesthesia. Turk J Anaesthesiol Reanim. 2017;45(5):277-281. doi:10.5152/TJAR.2017.68366
5. Hale N, Minzola D. Methylenetetrahydrofolate Reductase Deficiency: A Case Report. AANA J. 2020;88(4):303-306