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Nitrous Oxide B12 Mechanism — MRCPsych Paper B MCQ

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HardSubstance MisuseNitrous Oxide B12 MechanismMRCPsych Paper B

A 22-year-old man who has inhaled large quantities of nitrous oxide most days for 3 months develops distal paraesthesia, sensory ataxia and impaired joint-position sense. Spinal MRI shows symmetrical posterior-column signal abnormality. His serum vitamin B12 concentration, folate concentration, full blood count and renal function are normal, but methylmalonic acid and homocysteine concentrations are raised. Which molecular mechanism best explains his neurological syndrome?

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Correct answer: D — Oxidation of cobalamin's cobalt ion, inactivating methionine synthase and impairing myelin maintenance

Nitrous oxide oxidises the cobalt ion within cobalamin, functionally inactivating vitamin B12 and particularly inhibiting the B12-dependent enzyme methionine synthase. Impaired methionine and methylation pathways disrupt myelin maintenance, producing a myeloneuropathy resembling subacute combined degeneration. Total serum B12 may remain normal, so raised homocysteine and methylmalonic acid are important evidence of functional deficiency. Direct oligodendrocyte toxicity is not the established principal mechanism. Thiamine deficiency causes syndromes such as Wernicke encephalopathy rather than this characteristic posterior-column myelopathy. Folate metabolism may be secondarily disturbed, but primary dihydrofolate-reductase inhibition is not the mechanism. NMDA-receptor antagonism explains nitrous oxide's acute psychoactive and anaesthetic effects, not its chronic myeloneuropathy.

Reference: Paris A et al. Nitrous oxide-induced subacute combined degeneration of the cord: diagnosis and treatment. Practical Neurology. 2023;23:222–228. https://pn.bmj.com/content/23/3/222