Purine Nucleoside Phosphorylase Deficiency

Two immunodeficiency disorders are associated with 2 enzyme deficiencies of the purine salvage pathway that result in severe combined immunodeficiency (SCID). One of the disorders is known as adenosine deaminase (ADA) deficiency, and the other is purine nucleoside phosphorylase (PNP) deficiency.

ADA deficiency results in a T-, B-, and natural killer (NK)–cell form of SCID with marked lymphopenia. PNP deficiency causes decreased numbers of T cells and lymphopenia. Serum immunoglobulin (Ig) levels are normal to near-normal, but antibodies are deficient.

ADA and PNP deficiency are autosomal recessive disorders. In both disorders, the enzyme deficiencies result in accumulation of toxic metabolites. In ADA deficiency, the toxic metabolites block T-, B-, and NK-cell development; whereas in PNP deficiency, the metabolites are toxic to T-cell development. PNP deficiency is also associated with neurologic symptoms, including mental retardation and muscle spasticity, in 67% of patients. In addition, PNP deficiency is associated with increased risk of autoimmune disorders, such as autoimmune hemolytic anemia, immune thrombocytopenia, neutropenia, thyroiditis, and lupus.

Pathophysiology
PNP is an enzyme in the purine salvage pathway that metabolizes inosine and guanosine to hypoxanthine. In the preceding step of the pathway, ADA metabolizes adenosine to inosine. ADA deficiency causes an SCID that accounts for approximately 20% of all SCID cases. In both metabolic disorders, the enzyme deficiencies cause the accumulation of metabolites that are toxic to T and B cells.

In ADA deficiency, adenosine and adenine accumulate in the plasma. ATP accumulates in erythrocytes, and ADP, guanosine triphosphate (GTP), and ATP accumulate in lymphocytes. Deoxy-ATP (dATP) can reach toxic levels that inhibit ribonucleotide reductase, an enzyme essential for synthesis of DNA precursors.

In PNP deficiency, similar changes occur in elevated deoxy-GTP (dGTP) levels. dATP and dGTP predominantly accumulates in lymphoid tissue. dGTP inhibits ribonucleotide reductase, which is needed for synthesis of deoxynucleotides. In both ADA and PNP deficiencies, thymocytes are thought to be selectively destroyed because of elevated levels of dATP and dGTP.

In a further description of the mechanism of T-cell depletion in PNP deficiency in a murine model, Arpaia et al reported increased in vivo apoptosis of T cells and increased in vitro sensitivity to gamma irradiation.1 The immune deficiency in PNP deficiency may be the result of inhibited mitochondrial DNA repair due to the accumulation of dGTP in the mitochondria. The end result is increased sensitivity of T cells and thymocytes to spontaneous mitochondrial damage, leading to T-cell depletion due to apoptosis.

With ADA deficiency, destruction of resting T and B cells is increased. In comparison, PNP deficiency results in selective destruction of T cells, with little effect on B cells. Numerous mutations of the ADA gene (on chromosome 20) and PNP genes (on band 14q13) have been identified. PNP is a trimer with molecular weight of 84-94 kDa. Most identified mutations are missense mutations, but deletion is also described. All reported patients with homozygous mutations of PNP have been symptomatic. Because only small amounts of ADA are necessary for competent immunity, some patients with ADA mutations may still have 8-42% ADA activity and no profound immunodeficiency.

Frequency
United States
PNP deficiency is rare. PNP deficiency accounts for approximately 4% of all cases of combined immunodeficiency (CID), and ADA deficiency accounts for approximately 20% of all cases of CID.

International
The prevalence of primary immunodeficiency ranges from approximately 1 case per 54,000 population in Switzerland to 1 case per 200,000 population in Japan. CID accounts for 11-13% of all primary immunodeficiency disorders.

Mortality/Morbidity
Patients with PNP deficiency are at risk for life-threatening recurrent viral, bacterial, fungal, mycobacterial, and protozoal infections. In addition, failure to thrive eventually ensues.

The risk of lymphoma is also increased in patients with PNP deficiency.
Neurologic symptoms, including mental retardation and muscle spasticity, are major comorbid conditions that affect 67% of patients with PNP deficiency.
Bone marrow transplantation may cure the immunodeficiency but does not correct the neurologic disorder. Patients are at risk for autoimmune diseases, including autoimmune hemolytic anemia, immune thrombocytopenia, thyroiditis, neutropenia, and lupus.

Sex