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
Hereditary Orotic Aciduria; Uridine Monophosphate
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
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.
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
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.
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.
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.
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.