The neurological deterioration and death of a child with methylenetetrahydrofolate reductase (MTHFR) deficiency following anesthetization with nitrous oxide are reported from the University of Wisconsin Medical School, Madison, WI, and McGill University, Montreal. The child appeared normal until 3 months of age, when a mass in the left leg developed. The patient’s father, an uncle, and a sibling had elevated levels of homocysteine, and received high-dose vitamin B supplements. Twenty five days after resection of an infantile fibrosarcoma under halothane and 60% nitrous oxide anesthesia, the patient was readmitted because of seizures and episodic apnea. He was severely hypotonic, and areflexic. CT of brain showed generalized cerebral atrophy. Urine was positive for homocystine, but negative for organic acids and methylmalonic acid. Plasma homocystine was elevated, methionine level was low, vitamin B12 level normal, serum folate low normal, and csf folate normal. The patient died at 130 days of age (46 days after operation) with respiratory arrest. Autopsy revealed cerebral atrophy and severe demyelination, with astrogliosis in the midbrain, medulla, and cerebellum. Values for MTHFR activity in cultured fibroblasts were low. The child and his affected relatives were heterogeneous for a novel mutation which causes substitution of isoleucine for methionine. The mutation was transmitted from a paternal chromosome. Nitrous oxide inactivates methionine synthase and the enzyme inhibition is irreversible. 
COMMENT. Nitrous oxide irreversibly oxidizes the cobalt atom of vitamin B12, and inhibits the activity of methionine synthase which catalyzes the remethylation of 5-methyltetrahydrofolate and homocysteine to tetrahydrofolate and methionine. Activated methionine is the principal substrate for the assembly of the myelin sheath, for methyl substitutions in neurotransmitters, and DNA synthesis in tissues. (Chiang PK et al. 1996). The authors propose that a nitrous oxide-induced defect of methionine synthase coupled with the inherited defect of MTHFR were responsible for the patient’s death. They cite two recent case reports of infants with acute neurologic deterioration within days of nitrous oxide anesthesia. Both children had severe dietary cobalamin deficiency. The episodes were nonlethal. The above case ending in death followed two nitrous oxide anesthesias a few days apart, one for the biopsy and the other for tumor resection. In addition, the patient had an inborn error of metabolism involving MTHFR. Patients with MTHFR deficiency should not receive nitrous oxide anesthesia.