Orotic aciduria with megaloblastic anaemia unresponsive to B12/folate, WITHOUT hyperammonaemia, points to a deficiency of:

• A Carbamoyl phosphate synthetase II (CPS II)
• B Ornithine transcarbamoylase (OTC)
• C UMP synthase (bifunctional enzyme with OPRT and ODC activities) ✓
• D Dihydroorotase

Explanation

Hereditary orotic aciduria type I is caused by deficiency of UMP synthase, a bifunctional enzyme with orotate phosphoribosyltransferase (OPRT) and orotidine-5'-monophosphate decarboxylase (ODC) activities; this blocks the last two steps of de novo pyrimidine synthesis, causing orotic acid accumulation and pyrimidine deficiency (megaloblastic anaemia). Crucially, there is NO hyperammonaemia because the urea cycle (CPS I and OTC) is intact — distinguishing it from OTC deficiency, which also elevates orotic acid but with hyperammonaemia.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.