A 68-year-old vegetarian woman presents with a 4-month history of progressive symmetric leg weakness, gait ataxia, and paresthesias in stocking distribution. Examination reveals loss of vibration and proprioception in the feet, brisk knee reflexes but absent ankle reflexes, extensor plantar responses, and a positive Romberg sign. Laboratory findings show hemoglobin 9.4 g/dL, MCV 112 fL, hypersegmented neutrophils, serum B12 90 pg/mL, elevated methylmalonic acid and homocysteine, and positive intrinsic factor antibodies. MRI of the cervical spine shows symmetric T2 hyperintensity in the posterior columns with an inverted V sign on axial images. The pathophysiology marked as **A** in the diagram involves impaired myelin synthesis due to depletion of which critical methyl donor?

Explanation

## Why S-adenosylmethionine (SAM) is right In vitamin B12 deficiency, the enzyme methionine synthase cannot convert homocysteine to methionine without B12 as a cofactor. This blocks the generation of S-adenosylmethionine (SAM), the universal methyl donor in the body. SAM is essential for myelin methylation and the synthesis of myelin lipids; its depletion directly impairs myelin synthesis in the dorsal and lateral columns of the spinal cord, producing the characteristic inverted V sign of subacute combined degeneration (SCD). The clinical presentation—loss of vibration and proprioception (dorsal column signs), hyperreflexia and extensor plantars (lateral corticospinal tract signs), and ataxia (spinocerebellar involvement)—reflects this demyelination pattern. The elevated methylmalonic acid and homocysteine confirm the methionine synthase block. (Harrison 21e, Adams & Victor Neurology) ## Why each distractor is wrong - **Tetrahydrofolate (THF)**: While folate deficiency also causes megaloblastic anemia and elevated homocysteine, it does NOT cause elevated methylmalonic acid. The combination of elevated MMA + homocysteine is pathognomonic for B12 deficiency. Moreover, THF is not the primary methyl donor for myelin synthesis; SAM is. Giving folate alone in B12 deficiency can paradoxically worsen neurologic damage. - **Acetyl-CoA**: Although acetyl-CoA is involved in fatty acid synthesis, it is not the rate-limiting methyl donor in myelin formation. B12 deficiency does not primarily deplete acetyl-CoA; the block is at the methionine synthase step. Acetyl-CoA depletion would not explain the specific pattern of dorsal and lateral column demyelination. - **Succinyl-CoA**: Succinyl-CoA is the product of methylmalonyl-CoA mutase (the second B12-dependent enzyme), not the substrate. In B12 deficiency, methylmalonyl-CoA accumulates because it cannot be converted to succinyl-CoA. Accumulation of methylmalonyl-CoA and its metabolites (odd-chain fatty acids) contributes to myelin damage, but succinyl-CoA depletion is not the primary mechanism of demyelination in SCD. **High-Yield:** B12 deficiency → methionine synthase block → SAM depletion → impaired myelin methylation → dorsal + lateral column demyelination (SCD). Elevated MMA + homocysteine distinguishes B12 deficiency from folate deficiency. [cite: Harrison 21e — Megaloblastic Anemias; Adams & Victor Neurology]