Introduction
P5′N1 deficiency is one of the three most common causes of chronic hemolytic anemia caused by a red cell enzymopathy. It is less common than PK deficiency but has a similar frequency as GPI deficiency. It is inherited in an autosomal recessive manner.
Pathobiology
As the reticulocyte matures, ribosomes and RNA are degraded. P5′N1 assists in the process by catalyzing the dephosphorylation of pyrimidine nucleoside monophosphates into cytidine and uridine, which can diffuse across the cell membrane. P5′N1 activity is specific for pyrimidines and is much higher in reticulocytes than mature red cells. P5′N1 activity rapidly declines during the first few days of red-cell maturation. P5′N1 activity is dependent on Mg2+ and is inhibited by lead (Pb2+). Lead intoxication causes acquired P5′N1 deficiency with a hemolytic phenotype similar to hereditary P5′N1 deficiency.
Thus far, more than 50 different mutations in over 100 patients have been reported in P5′N1 deficiency. Most patients are homozygous and consanguinity is common.
The accumulation of pyrimidines in RBCs because of a deficiency of P5′N1 is presumed to be toxic, although the exact mechanism by which P5′N1 causes hemolysis is unknown. Deficiency of P5′N1 is at least partly compensated in vivo by other nucleosidases or other nucleotide metabolic pathways.
Clinical and Laboratory Features
P5′N1 deficiency causes chronic hemolytic anemia, with severity ranging from compensated hemolysis without anemia to transfusion dependent anemia. Ribosomal aggregates are visible in RBCs as coarse basophilic stippling. This basophilic stippling of RBCs is a laboratory hallmark of P5′N1 deficiency, and thus morphologic examination of the peripheral blood smear provides simple and inexpensive screening. However basophilic stippling is not a specific finding, as it is also found in hemolytic anemia caused by acute lead toxicity and in some sideroblastic anemias. The nucleotides of normal red cells consist largely of purine derivatives (which have an absorption maximum at approximately 260 nm) with very low levels of pyrimidine nucleotides (absorption at 280 nm). In P5′N1 deficiency, high levels of pyrimidine nucleotides accumulate in erythrocytes, resulting in a decrease in the OD260:OD280 absorbance ratio. Confirmation of the diagnosis requires demonstration of decreased P5′N1 activity, normal blood lead levels and, if feasible, high concentrations of pyrimidine nucleotides in red cells.
Therapy
Chronic transfusion support may be necessary for severe cases. Milder cases may require transfusion only periodically during pregnancy, infection, or other stressors. Iron overload may occur, as in any chronic hemolytic condition, and iron chelation may be needed. Splenectomy was reported to be beneficial in several cases.
