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Very rare congenital disorder characterized by an inborn error of pyrimidine metabolism resulting in hematologic (megaloblastic anemia unresponsive to vitamin C, vitamin B12, or folic acid) and neurologic (growth and mental retardation) manifestations. Onset in childhood.

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Hereditary Orotic Aciduria; Uridine Monophosphate Synthase Deficiency.

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There are two clinical types: type I, which is a deficiency of the OMP-PP portion of uridine monophosphate synthetase, and type II, which is a deficiency of the OMP-DC portion of uridine monophosphate synthetase.

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Autosomal recessive. Genetic defect is described as a deficiency of OMP-PP and/or OMP-DC activities, accumulation of orotic acid, plus interference with RNA and DNA synthesis, leading to hematologic manifestations because vigorous synthesis of RNA and DNA is necessary for normal hematopoiesis.

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Uridine monophosphate synthase is a bifunctional enzyme involved in the de novo synthesis of pyrimidines. A first reaction catalyzed by orotate phosphoribosyltransferase converts orotic acid into orotidine monophosphate; the second, catalyzed by orotidine decarboxylase, transforms orotidine monophosphate into uridine monophosphate. The classic type I disease is caused by diminished activity of both enzymes; type II disease could be caused by diminished activity of orotidine decarboxylase only.

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Urinalysis shows massive oversecretion of orotic acid (up to 1.5 g/day) and crystalluria. However, orotic aciduria can also result from some urea cycle defects, parenteral nutrition, or essential amino acid deficiency. The enzymatic diagnosis can be performed on red blood cells. A deficiency of orotidylic acid pyrophosphorylase and/or decarboxylase activities in leukocytes, erythrocytes, hepatic cells, and cultured skin fibroblasts is characteristic. The presence in the serum of megaloblastic anemia is typical.

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Megaloblastic anemia with anisocytosis and hypochromia appearing a few weeks or months after birth is the first manifestation. It does not respond to iron, folic acid, or vitamin B12. If the disorder is unrecognized, failure to thrive with growth and developmental retardation ensues. Urinary obstruction (renal, ureteral, or urethral) from orotic acid crystals has been reported. For treatment, the enzymatic defect can be bypassed by the administration of uridine, which is converted into uridine monophosphate by uridine kinase. The hematologic response is quick. The dosage is adapted in order to achieve the lowest possible urinary output of orotic acid.

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Check hemoglobin level.

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Perioperative hydration should be sufficient to maintain a high urine output to prevent increasing the urinary concentration of orotic acid and the ensuing risk of urinary stones.

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No specific implications.

Van den Berghe G, Vincent M-F, Marie S: Disorders of purine and pyrimidine metabolism, in Fernandes J, Saudubray J-M, van den Berghe G (eds): Inborn Metabolic Diseases. 3rd ed. Berlin, Springer, 2000, p 355.

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