The presentation of failure to thrive, refractory megaloblastic anemia, crystalluria, and a normal blood ammonia level is suggestive of defective UMP synthase in the de novo pyrimidine synthesis pathway resulting in orotic aciduria.
Orotic aciduria is an autosomal recessive disorder resulting from a defect in the bifunctional enzyme UMP synthase (orotate phosphoribosyltransferase and orotidine-5'-phosphate decarboxylase) that prevents the conversion of orotic acid to uridine monophosphate (UMP). This inability to produce UMP prevents the de novo synthesis of pyrimidine bases; therefore, there is a lack of pyrimidine bases and DNA cannot replicate. In ornithine transcarbamoylase (OTC) deficiency, there is also a build up of orotic acid, but OTC deficiency also presents with hyperammonemia, which is missing in orotic aciduria.
Nyhan reviews the disorders of purine and pyrimidine metabolism. Orotic aciduria is a defect in the de novo pyrimidine pathway leading to a deficiency of pyrimidine bases needed for DNA replication. Errors in both purine and pyrimidine metabolism can result in a marked susceptibility to infection and even immunodeficiency in the cases of pyrimidine salvage pathway defects.
Bailey discusses the different subtypes of orotic aciduria all resulting from a defect in UMP synthase. By using the ratio of urinary excretion of orotidine to orotate, one can determine the particular forms of the enzymatic defect.
Figure A shows a blood smear with macrocytosis and the characteristic hypersegmented neutrophils with up to 8 lobes versus the normal 3 to 4.
Illustration A demonstrates a normal blood smear with a normally segmented neutrophil with 3 to 4 lobes.
Illustration B shows the normal pathway of UMP synthesis which is disrupted in orotic aciduria.
Answer A: Ornithine transcarbamoylase (OTC) is involved in the urea cycle catalyzing the reaction between carbamoyl phosphate and ornithine to form citrulline. Patients with OTC deficiency present with a decreased BUN, elevated orotic acid levels in the blood and urine with symptoms of hyperammonemia.
Answer B: Adenosine deaminase (ADA) is involved in the conversion of adenosine to inosine. Patients with a deficiency in ADA present with a decrease in lymphocytes and have severe combined immunodeficiency disease (SCID).
Answer C: Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is involved in the purine salvage pathway converting guanine to guanylic acid and hypoxanthine to inosinic acid. Patients with a deficiency in HGPRT present with an increase in uric acid in the blood and urine and display symptoms of gout, aggression, retardation, and self-mutilation.
Answer D: Xanthine oxidase is involved in the conversion of hypoxanthine to xanthine and finally to uric acid. Although a very rare condition, patients with a deficiency in xanthine oxidase have high levels of xanthine in the blood and urine and can present with xanthine kidney stones and renal failure.
Nyhan WL. Disorders of purine and pyrimidine metabolism. Mol Genet Metab. 2005 Sep-Oct;86(1-2):25-33. Review.
PMID:16176880 (Link to Abstract)
Bailey CJ. Orotic aciduria and uridine monophosphate synthase: a reappraisal. J Inherit Metab Dis. 2009 Dec;32 Suppl 1:S227-33. doi: 10.1007/s10545-009-1176-y. Epub 2009 Jun 27. Review.
PMID:19562503 (Link to Abstract)