Hereditary Orotic Aciduria: UMP Synthase Deficiency and Uridine Treatment
The Bifunctional Protein Deficiency
The bifunctional enzyme UMP synthase (also called uridine 5'-monophosphate synthase) is deficient in patients with megaloblastic anemia unresponsive to vitamin B12 or folic acid. 1 This enzyme catalyzes the final two steps of de novo pyrimidine synthesis, converting orotic acid to uridine monophosphate (UMP). 1
Clinical Presentation
- Patients present with megaloblastic anemia that fails to respond to standard vitamin supplementation 1
- Significantly elevated urinary orotic acid levels are the hallmark diagnostic finding 1
- Hematologic abnormalities include megaloblastic anemia (documented in 15 of 19 published cases), leukopenia (8 cases), and neutropenia (at least 2 cases) 1
- Growth retardation is common, with weight and height typically at or below the lower limit of normal for age 1
Distinguishing from Vitamin Deficiencies
This condition must be differentiated from B12 and folate deficiency, which are the most common causes of megaloblastic anemia. 2, 3, 4 The key distinguishing feature is the lack of response to vitamin supplementation and the presence of markedly elevated urinary orotic acid. 1
Why Uridine is Effective Treatment
Uridine bypasses the defective UMP synthase enzyme by providing exogenous pyrimidine nucleotides directly, allowing DNA synthesis to proceed normally. 1
Mechanism of Action
- The deficient UMP synthase enzyme normally converts orotic acid → orotidine → UMP 1
- When this pathway is blocked, cells cannot synthesize pyrimidines de novo, leading to impaired DNA synthesis 5
- Exogenous uridine is phosphorylated to UMP by salvage pathways, completely bypassing the defective enzyme 1
- This restores the pyrimidine nucleotide pool needed for DNA synthesis and erythropoiesis 5
Clinical Evidence of Efficacy
- Hematologic improvement occurs within 2-3 weeks of initiating uridine replacement therapy in almost all documented cases when administered in sufficient amounts 1
- Urinary orotic acid concentrations are significantly reduced within 1-2 weeks of starting treatment 1
- Improvements in body weight are documented over time with continued therapy 1
- The therapeutic effects are maintained over months and years as long as treatment continues at sufficient doses 1
Treatment Requirements
- Lifelong treatment is required - hematologic abnormalities and orotic aciduria reappear within days to 2-3 weeks when uridine is stopped or the dose is reduced 1
- Doses must be adjusted based on body weight increases to maintain efficacy 1
- If absolute dosages are not adjusted adequately for weight gains, signs and symptoms recur 1
FDA-Approved Formulation
XURIDEN (uridine triacetate) oral granules are FDA-approved for hereditary orotic aciduria, providing 2 grams of uridine triacetate per packet. 1 The dose is prescribed based on body weight and can be mixed with food or liquids. 1
Critical Pitfall
Never administer folic acid before ruling out B12 deficiency in megaloblastic anemia, as folic acid may mask anemia while allowing irreversible neurological damage to progress. 6 However, in hereditary orotic aciduria specifically, neither B12 nor folate will be effective since the defect is in pyrimidine synthesis, not folate/B12 metabolism. 1