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?

Question

Accepted Answer

A. Deficiency of methylmalonyl-CoA mutase enzyme. ## 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.

Answer

B. Pernicious anemia due to autoimmune gastritis

Answer

C. Malabsorption secondary to celiac disease

Answer

D. Dietary deficiency of vitamin B12 in strict vegetarians

Explanation

Causes of Megaloblastic Anemia

Recognized Causes of B12-Deficient Megaloblastic Anemia

Why Methylmalonyl-CoA Mutase Deficiency Is NOT Correct

Pathophysiology of B12-Mediated Megaloblastosis

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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