Pyrimidine-5’-nucleotidase deficiency

Fig. 6. Basophilic stippling in peripheral blood smear of a patient with pyrimidine 5 -nucleotidase deficiency.

V4. Valentine, W. N., Fink, K Paglia, D. E., Harris, S. R., and Adams, W. S., Hereditary hemolytic anemia with human erythrocyte pyrimidine 5 -nucleotidase deficiency. J. Clin. Invest. 54, 866-879 (1974). 

Bianchi P, Fermo E, Alfinito F, Vercellati C, Baserga M, Ferraro F, et al. Molecular characterization of six unrelated Italian patients affected by pyrimidine 5 -nucleotidase deficiency. Br J Haematol 2003 122 847-51. 

Marinaki AM, Escuredo E, Duley JA, Simmonds HA, Amici A, Naponelli V, et al. Genetic basis of hemolytic anemia caused by pyrimidine 5 nucleotidase deficiency. Blood 2001 97 3327-32. 

Rees DC, Duley JA, Marinaki AM. Pyrimidine 5 nucleotidase deficiency. Br J Haematol 2003 120 375-83. 

DIAGNOSTIC AND THERAPEUTIC APPROACHES IN PYRIMIDINE 5 -NUCLEOTIDASE DEFICIENCY... 

Fig. 1 shows such a separation in a PGA extract of H-Uridine labelled erythrocytes from a patient with pyrimidine 5 nucleotidase deficiency. Peaks corresponding in elution time to uridine and cytidine mono-, di-, and tri-phosphates can be seen. Label is present in all three uridine nucleotide peaks as well as in a fourth peak which corresponds in elution time in these and under other separation conditions with UDP-glucose (UDPG). 

In summary, it is proposed that the most hopeful prospect for therapy of this condition would be to search for a specific inhibitor of orotate transport across cell membranes. This is likely to affect the metabolism of pyrimidines in only two tissues, liver and erythrocytes, and, unless it gives rise to toxic accumulations of orotate in the liver, could help to reduce pyrimidine nucleotide levels in pyrimidine 5 nucleotidase deficient erythrocytes. A trial of a specific inhibitor of uridine kinase might also be appropriate, and the final choice of a therapeutic approach will depend on the demonstration of which of these two alternative pathways amenable to therapeutic intervention contributes most to erythrocyte pyrimidine nucleotide accumulation. 

Harley, E. H., Heaton, A., and Wicomb, W., 1978, Pyrimidine metabolism in hereditary erythrocyte pyrimidine 5 -nucleotidase deficiency. Metabolism, 27 1743. 

Torrance, J. D., and Whittaker, D., 1979, Distribution of erythrocyte nucleotides in pyrimidine 5 -nucleotidase deficiency, Brit. J. Haematol., 43 423. 

Adams, W. S., 1974, Hereditary hemolytic anaemia with human erythrocyte pyrimidine 5 -nucleotidase deficiency, J. Clin. Invest., 54 866. 

The uptake of the pyrimidine nucleotide precursor, orotate, by non-nucleated human erythrocytes is not immediately explicable, (l). During the course of an investigation into the origin of the increased erythrocyte nucleotides seen in hereditary gythrocyte pyrimidine 5 nucleotidase deficiency, rapid uptake of C orotate and its conversion to uridine nucleotides by normal red cells was observed (Figure 1(a) A). Moreover, free uridine was present within the cells and accumulated in significant quantities in the medium (Figure 2). 

Fig, 2. Nucleotidase isozymes in erythrocytes from the patient with pyrimidine 5 -nucleotidase deficiency ( ) and five healthy controls (1-5) detected using cytidine monophosphate (CMP), thymidine monophosphate (dTMP), deoxycytidine monophosphate (dCMP) as substrates. 

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