A 40-year-old man with type 2 diabetes has a macrocytic anemia that does not respond to vitamin B12 or folate. Urinary orotic acid is markedly elevated. The enzyme defect underlying this megaloblastic anemia lies at which step?
- A De novo synthesis of pyrimidines, before the step blocked by methotrexate ✓
- B Conversion of dUMP to dTMP
- C Conversion of homocysteine to methionine
- D Purine salvage via HGPRT
Correct answer: A. De novo synthesis of pyrimidines, before the step blocked by methotrexate
Explanation
Hereditary orotic aciduria results from UMP synthase deficiency, blocking conversion of orotic acid to UMP in pyrimidine synthesis. Accumulated orotic acid impairs DNA synthesis, producing megaloblastic anemia refractory to B12 and folate, often with failure to thrive. Lesch Nyhan (HGPRT) causes hyperuricemia and self-mutilation without megaloblastosis, so option D fails.
Reference: Nelson Textbook of Pediatrics, 21st ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.