Hereditary orotic aciduria (UMPS deficiency)

• Autosomal recessive, UMPS (uridine monophosphate synthase), a bifunctional enzyme carrying both orotate phosphoribosyltransferase and orotidine-5'-monophosphate decarboxylase activity
• The block is in de novo pyrimidine synthesis, so orotic acid accumulates and downstream pyrimidines (UMP, and therefore CTP and TTP) are not made
• Very rare, on the order of a few dozen reported families

• Megaloblastic anemia unresponsive to B12 and folate. This is the finding that should trigger the diagnosis, because every common cause of megaloblastic anemia responds to one or the other
• Failure to thrive, developmental delay
• Orotic acid crystalluria, which can cause urinary obstruction and nephropathy
• Immunodeficiency with recurrent infections in a subset (pyrimidines are needed for lymphocyte proliferation)
• Normal serum ammonia

• Urine orotic acid, markedly elevated
• Normal ammonia, normal plasma amino acids
• Confirm with UMPS sequencing or enzyme assay in erythrocytes

The discriminator that matters

Orotic aciduria has two very different causes, and ammonia separates them:

In OTC deficiency, carbamoyl phosphate that cannot enter the urea cycle spills into the pyrimidine pathway and is shunted to orotic acid. The pyrimidine pathway itself is intact, so there is no anemia.

• Oral uridine, given as uridine triacetate. The response is dramatic: the anemia corrects, growth resumes, and orotic acid excretion falls
• Lifelong therapy; relapse follows interruption
• Monitor for urinary tract obstruction from crystals before treatment takes effect