Purine Nucleoside Phosphorylase Deficiency

A number sign (#) is used with this entry because purine nucleoside phosphorylase deficiency is caused by mutation in the PNP gene (164050).

Description

Purine nucleoside phosphorylase deficiency is a rare autosomal recessive immunodeficiency disorder characterized mainly by decreased T-cell function. Some patients also have neurologic impairment (review by Aust et al., 1992).

Clinical Features

Hagberg et al. (1970) described brother and sister with ataxic diplegia and defective cellular immunity. At age 15 months, the sister had vaccinia gangrenosa, which was successfully drug-treated. She died of generalized varicella at age 4.5 years. The brother died at age 5 years of brain abscess.

Giblett et al. (1975) reported a child with severely defective T-cell immunity and normal B-cell immunity associated with absence of red cell nucleoside phosphorylase. The parents were consanguineous, and each showed less than half the normal activity of the enzyme in their red cells (Berglund et al., 1975). Deficiency of adenosine deaminase (608958), the next enzyme in the pathway, results in severe combined immune deficiency (SCID; 102700).

Cohen et al. (1976) reported a girl with purine nucleoside phosphorylase deficiency and immune defect who had severe hypouricemia and hypouricosuria, but excessive amounts of purines (mainly inosine and guanosine) in the urine. Patient erythrocytes, but not cultured fibroblasts, contained increased concentrations of phosphoribosylpyrophosphate and inosine. The metabolic abnormalities resembled those in the erythrocytes of patients with the Lesch-Nyhan syndrome (300322). The immune defect was thought to be related to inhibition of adenosine deaminase by inosine.

Stoop et al. (1977) studied a 15-month-old girl, 2 sisters of whom had died of immunodeficiency. PNP was lacking from red cells and lymphocytes. The parents and a normal brother had intermediate levels. Both T cells and B cells were normal at birth, but thereafter a gradual decrease in T-cell immunity occurred. The patient showed high inosine and guanosine levels in the blood, as well as hypouricemia and hypouricosuria. She also had spastic tetraparesis.

In a patient with severely defective T-cell function and normal B-cell function, Osborne et al. (1977) found no detectable red cell PNP and no detectable immunologically reactive material. The parents, second cousins, had less than half the normal enzyme activity. Two patients in a second family had 0.5% residual enzyme activity and about half-normal immunologically reactive material. The parents, who were not related, showed electrophoretically different mutant enzymes that were also different from those in the first family. The findings indicated that the affected children in the second family were genetic compounds, not true homozygotes.

The immune defect from PNP deficiency is often accompanied by a neurologic disorder. Watson et al. (1981) reported a 2.5-year-old boy with the disorder who died of malignant lymphoma of the B-immunoblastic type, who also had spastic tetraplegia.

Rijksen et al. (1987) described a case in a 3-year-old boy who was admitted for investigation of a behavioral disorder and spastic diplegia. Severe lymphopenia was found; however, clinical symptoms of immune deficiency did not become apparent until the age of 4 years.

Stephenson and Tolmie (1990) stated that the family reported by Graham-Pole et al. (1975) as having 'familial dysequilibrium-diplegia with T-lymphocyte deficiency' turned out to have PNP deficiency. The condition was diagnosed retrospectively from stored fibroblasts from an affected child and from demonstration that both parents had half-normal activity of PNP. Stephenson and Tolmie (1990) were prompted to restudy this family after diagnosing PNP deficiency in a young girl who presented with dysequilibrium syndrome with pyramidal signs, including extensor plantar responses and exaggerated reflexes but not prominent spasticity, very similar to the neurologic picture in the family reported by Graham-Pole et al. (1975). The child had defective cell-mediated immunity and died of lymphoma shortly after her third birthday.

Dalal et al. (2001) reported a 4.5-year-old boy, born of a Caucasian father and Japanese mother, who had immunodeficiency associated with a mild delay in gross motor development. Although he did not have severe infections in infancy, he experienced an uneventful varicella infection at age 8 months, and was referred at age 26 months after a prolonged parvovirus infection that induced pure red cell aplasia. Physical examination showed mild ataxia and delayed speech and motor development. Laboratory studies showed normal immunoglobulins, but decreased number of T cells and reduced mitogenic responses. PNP enzyme activity was essentially undetectable; PNP activity in the parents and 2 healthy sisters was about half of control values.

Pathogenesis

Mitchell et al. (1978) found that deoxyadenosine and deoxyguanosine are particularly toxic to T cells but not to B cells. Addition of deoxycytidine or dipyridamole prevented deoxyribonucleoside toxicity.

In T cells, the absence of PNP activity is thought to lead to an accumulation of deoxyguanosine triphosphate, which inhibits the enzyme ribonucleotide reductase (Mitchell et al., 1978; Ullman et al., 1979). This inhibition blocks DNA synthesis, thereby preventing the cellular proliferation required for an immune response.

Although early studies suggested that B-cell function is normal or even increased in PNP deficiency, later studies showed that B-cell function can be disrupted as well (Markert, 1991). This was the case in a patient in whom the nature of the molecular defects was demonstrated by Aust et al. (1992): she had normal B-cell counts but significantly depressed immunoglobulin levels.

Molecular Genetics

In a patient with nucleoside phosphorylase deficiency, Williams et al. (1987) identified a homozygous mutation in the PNP gene (E89K; 164050.0001).

Aust et al. (1992) identified compound heterozygosity for 2 mutations in the PNP gene (D128G, 164050.0003; R234P, 164050.0004) in a patient with nucleoside phosphorylase deficiency.

In a patient with PNP deficiency, Dalal et al. (2001) identified compound heterozygosity for 2 mutations in the PNP gene (164050.0009; 164050.0010).

Animal Model

By male germ cell mutagenesis, Snyder et al. (1997) recovered 3 point mutations in the Pnp gene. These were, in order of increasing order of severity of enzyme deficiency and phenotype, met87 to lys, ala228 to thr, and trp16 to arg. A marked decline in total cell numbers per thymus occurred between 2 and 3 months for the 2 more severe mutants (35% and 52%, respectively) and by 8 months for the least severe mutation. Spleen lymphocyte Thy-1(+) cells were reduced by 50% and spleen lymphocyte response to T-cell mitogen and interleukin-2 was reduced by 80%. The Pnp-deficient mouse exhibited age-dependent progressive perturbations in thymocyte differentiation, reduced numbers of thymocytes, and reduced splenic T-cell numbers and response. The progressive T-cell deficit was similar to that observed in the human disorder.