A child presents with megaloblastic anemia, orotic aciduria, and poor growth. There is no hyperammonemia. Which enzyme deficiency is MOST likely responsible?

• A Ornithine transcarbamylase (OTC)
• B Carbamoyl phosphate synthetase II (CPS II)
• C UMP synthase (bifunctional: orotate phosphoribosyltransferase + OMP decarboxylase) ✓
• D Dihydroorotase

Explanation

Hereditary orotic aciduria (type I) is caused by deficiency of UMP synthase, which has two activities: orotate phosphoribosyltransferase (converting orotate to OMP) and OMP decarboxylase (converting OMP to UMP). Without UMP synthesis, pyrimidine starvation causes megaloblastic anemia; orotate accumulates and is excreted in urine. Crucially, there is no hyperammonemia (ruling out urea cycle defects like OTC deficiency, which also causes orotic aciduria but with hyperammonemia). Treatment is with uridine supplementation.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.