A 52-year-old woman from rural India presents with progressive fatigue, glossitis, and paresthesias in her feet for 3 months. Blood film shows hypersegmented neutrophils and macro-ovalocytes. Serum vitamin B12 is low, and intrinsic factor antibodies are negative. Which of the following is NOT a recognized cause of megaloblastic anemia in this clinical context?

Explanation

## Causes of Megaloblastic Anemia **Key Point:** Megaloblastic anemia results from impaired DNA synthesis due to deficiency of vitamin B12 or folate. The underlying mechanisms are well-characterized and relate to nucleotide metabolism, not amino acid metabolism. ### Recognized Causes of B12-Deficient Megaloblastic Anemia | Cause | Mechanism | Clinical Context | |-------|-----------|------------------| | Pernicious anemia | Autoimmune destruction of gastric parietal cells → ↓ intrinsic factor | Most common in temperate regions; associated with other autoimmune diseases | | Dietary deficiency | Inadequate intake (vegans, strict vegetarians) | Common in India; no animal product consumption | | Malabsorption | Celiac disease, tropical sprue, Crohn's disease, post-gastrectomy | Impaired ileal absorption | | Transcobalamin II deficiency | Rare genetic disorder affecting B12 transport | Presents in infancy/early childhood | | Nitrous oxide abuse | Inactivates methionine synthase cofactor | Occupational or recreational exposure | ### Why Methylmalonyl-CoA Mutase Deficiency Is NOT Correct **High-Yield:** Methylmalonyl-CoA mutase is a **biotin-dependent enzyme** involved in propionate metabolism (amino acid and odd-chain fatty acid catabolism), NOT in nucleotide synthesis. Its deficiency causes methylmalonic acidemia (elevated methylmalonic acid in urine and serum), a separate metabolic disorder unrelated to megaloblastic anemia. **Clinical Pearl:** While vitamin B12 *is* a cofactor for methylmalonyl-CoA mutase (and methionine synthase), the enzyme deficiency itself does not cause megaloblastic anemia. B12 deficiency causes megaloblastic anemia through impaired thymidylate synthase activity and folate metabolism, not through methylmalonic-CoA mutase dysfunction. ### Pathophysiology of B12-Mediated Megaloblastosis 1. B12 is a cofactor for **methionine synthase** (converts homocysteine → methionine) 2. B12 deficiency → ↓ methionine → ↓ S-adenosylmethionine (SAM) 3. ↓ SAM → impaired methylation of deoxyuridine monophosphate (dUMP) → dTMP 4. ↓ dTMP → impaired DNA synthesis → megaloblastic changes (nuclear-cytoplasmic asynchrony) **Warning:** Do not confuse methylmalonic acidemia (a separate inborn error of metabolism affecting the methylmalonyl-CoA mutase pathway) with megaloblastic anemia.