Clinical Information

Pyrimidine 5' nucleotidases (P5'Ns) are catabolic enzymes that regulate cellular nucleotide and nucleoside levels through the dephosphorylation of noncyclic nucleoside 5'-monophosphates. P5'N activity is much higher in reticulocytes than in aged red blood cells due to increased demand during erythroid maturation. Reticulocyte ribosomal RNA degradation results in pyrimidine nucleotide residues that require conversion to nucleosides to allow diffusion outside the cell. Disruption of this process results in intracellular pyrimidine nucleotide accumulation visible as coarse basophilic stippling.

Several different 5'-nucleotidase enzymes have been identified with distinctive substrate specificity, cellular localization, and tissue distribution. Only P5'N type 1 is known to be associated with P5'N deficiency (also called uridine 5' monophosphate hydrolase deficiency), a cause of congenital nonspherocytic hemolytic anemia (OMIM 266120, autosomal recessive). The disorder manifests as mild/compensated to moderate hemolytic anemia with persistent reticulocytosis. Additional features include jaundice/neonatal hyperbilirubinemia, splenomegaly, and characteristic marked basophilic stippling on the peripheral blood smear. Coincident hemoglobin E may lead to a more severe hemolytic anemia.

P5'N deficiency is caused by homozygous or compound heterozygous alterations in the NT5C3A gene, mapped to chromosome 7p14. Assaying for the presence of pyrimidine nucleotides serves as a surrogate marker for P5'N deficiency and is not specific for a diagnosis of hereditary P5'N deficiency. Enzyme function is magnesium ion-dependent and is inhibited by metal chelating reagents, such as EDTA. Activity is inhibited by heavy metal ions including lead, mercury, copper, nickel, and cadmium, and toxic levels can cause accumulation of intracellular pyrimidine nucleotides.