The smear looks the same every time. What differs is where the thymidine supply broke, and the stem gives it away with one lab value.
A 64-year-old woman has months of fatigue and numb, tingling feet. She has a smooth red tongue and loses her balance when she closes her eyes. MCV is 114 fL with pancytopenia. The smear shows macro-ovalocytes and neutrophils with six lobes. LDH and indirect bilirubin are high. A resident starts folic acid and her blood count improves.
Why is that a mistake, and what should have been checked first?
Thymidylate synthase turns dUMP into dTMP, using N5,N10-methylene-THF as the one-carbon donor. RNA and protein synthesis carry on, because they do not need thymine. DNA synthesis stalls. The nucleus matures slowly while the cytoplasm keeps growing, so the cell comes out large with an immature nucleus. That mismatch is nuclear-cytoplasmic asynchrony.
Methionine synthase needs B12 to pass the methyl group from 5-methyl-THF to homocysteine. Without B12, 5-methyl-THF piles up and cannot go back. Folate is present but stuck, so the cell is functionally folate-deficient.
Pernicious anemia (anti-intrinsic factor), ileal disease, fish tapeworm, strict veganism, metformin.
The tetrahydrofolate pool runs dry, so there is no methylene-THF for thymidylate synthase. B12 is normal, so methylmalonyl-CoA mutase works and the myelin stays healthy.
Alcohol use, pregnancy, phenytoin, celiac disease or sprue, methotrexate, a diet with no greens.
Intake is normal and the machinery is faulty. Infants present early, and the lab pattern tells you which step failed.
The block sits upstream of both vitamins. UMP synthase cannot turn orotic acid into UMP, so there is no pyrimidine to make dTMP. Autosomal recessive, with failure to thrive.
Treatment is uridine. It supplies UMP through salvage and shuts down orotic acid production by feedback.
One lesson by email, same four questions each time.
Browse all topics