Hereditary orotic aciduria

Hereditary orotic aciduria (also known as UMP synthase deficiency, orotic aciduria type I, or uridine monophosphate synthase deficiency) is an extremely rare autosomal recessive disorder of pyrimidine metabolism caused by mutations in the UMPS gene, which encodes the bifunctional enzyme uridine 5'-monophosphate synthase. This enzyme catalyzes the last two steps of the de novo pyrimidine biosynthesis pathway. When deficient, orotic acid accumulates in the blood and is excreted in large amounts in the urine, while downstream pyrimidine nucleotides are inadequately produced. The disease primarily affects the hematologic system and growth. Affected infants typically present with severe megaloblastic anemia that is unresponsive to vitamin B12 and folate supplementation, failure to thrive, and developmental delay. Crystalluria due to excessive urinary orotic acid excretion may also occur, potentially leading to urinary tract obstruction. Immune dysfunction has been reported in some cases. Without treatment, the condition can be life-threatening. Treatment consists of oral uridine supplementation, which bypasses the metabolic block by providing the necessary pyrimidine nucleotide precursor. Uridine therapy effectively corrects the megaloblastic anemia, reduces orotic acid excretion, and improves growth and development. Early diagnosis and initiation of lifelong uridine replacement therapy are essential for a favorable outcome. Fewer than 20 cases have been reported worldwide, making this one of the rarest known inborn errors of metabolism.

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