Orotic aciduria (type 1) presents with megaloblastic anaemia that does NOT respond to vitamin B12 or folate. The enzyme defect involves:
- A Dihydroorotase, preventing formation of dihydroorotate from carbamoyl aspartate
- B PRPP synthetase overactivity driving excess pyrimidine production
- C UMP synthase (bifunctional enzyme: OPRT + ODC), blocking pyrimidine de novo synthesis ✓
- D Thymidylate synthase deficiency blocking dTMP synthesis
Correct answer: C. UMP synthase (bifunctional enzyme: OPRT + ODC), blocking pyrimidine de novo synthesis
Explanation
Type 1 hereditary orotic aciduria is caused by deficiency of UMP synthase — a bifunctional enzyme with orotate phosphoribosyltransferase (OPRT) and orotidine-5'-monophosphate decarboxylase (ODC) activities. Both activities are encoded on the same polypeptide. Orotic acid accumulates proximal to the block and is excreted in urine. Pyrimidine starvation causes megaloblastic anaemia not responsive to B12/folate. Treatment is uridine supplementation (bypasses the block).
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.