Search for a rare disease
Other search option(s)
Purine nucleoside phosphorylase deficiency
A rare immune disease characterized by progressive immunodeficiency leading to recurrent and opportunistic infections, autoimmunity and malignancy as well as neurologic manifestations.
ORPHA:760Classification level: Disorder
To date, more than 70 patients have been reported with Purine nucleoside phosphorylase (PNP) deficiency in the world literature. PNP deficiency accounts for less than 4% of patients with severe combined immunodeficiency (SCID).
PNP deficiency typically manifests in the 1st years of life, with recurrent, opportunistic infections caused by bacterial, viral (such as varicella zoster virus), and fungal (such as Pneumocystis carinii) pathogens. The susceptibility to infections is variable ranging from classical SCID in infancy to infrequent infections during childhood and even the 2nd decade of life. Failure to thrive has also been reported. Up to 2/3 of patients have neurologic involvement including motor system dysfunction, hyper/hypotonia, spastic paresis, ataxia, hyperactivity, and behavioral problems. Cerebrovascular accidents and sensorineural deafness are less commonly observed. The neurologic involvement often precedes immune abnormalities. Autoimmune manifestations are reported in 1/3 of cases and include autoimmune hemolytic anemia, immune thrombocytopenic purpura and systemic lupus erythematosus.
PNP deficiency is caused by loss-of-function mutations in the PNP gene (14q11.2) which encodes a key enzyme (PNP) in the purine salvage pathway. PNP is vital for removal of metabolites of DNA breakdown and promotes recycling of purine bases. Lack of PNP allows intracellular accumulation of such metabolites which are particularly toxic to immature lymphoid cells, leading to lymphopenia and impaired cell-mediated immunity. Intracellular accumulation of purine bases has also been suggested to cause neuronal cell apoptosis.
Diagnosis is based on the clinical examination and on laboratory findings showing leukopenia, severe lymphopenia with low CD3, CD4, and CD8 counts and variable B cell function and immunoglobulin levels. Neutropenia has also been reported. Hallmark diagnostic markers of PNP deficiency include hypouricemia, complete or near complete absence of PNP activity in red blood cell lysate and increased urine or blood levels of inosine, guanosine and their deoxy forms. Diagnosis is confirmed by genetic screening of PNP.
Differential diagnosis includes aplastic anemias, SCID, severe combined immunodeficiency due to adenosine deaminase deficiency, ataxia-telangiectasia, and viral meningoencephalitis.
Measurement of T cell receptor excision circles during newborn screening for SCID can detect some patients suffering from PNP deficiency, although removal of metabolites by maternal PNP may delay the deleterious effects on PNP-deficient lymphocytes. Few newborn screening programs also measure purine metabolites in dried blood spots.
Transmission is autosomal recessive. Genetic counseling should be proposed to affected families informing them of a 25% risk of transmitting the disease where both parents are unaffected carriers.
Management and treatment
Specific enzyme replacement is not available for PNP deficiency, although frequent red blood cells transfusions rich in PNP have been shown to provide temporary benefit. Hematopoietic stem cell transplantation (HSCT) is the only treatment option for the severe immune deficiency. Transplanted cells deliver the missing enzyme, thereby improving purine homeostasis. Supportive treatment, including intravenous immunoglobulin therapy, prophylaxis for Pneumocystis carinii, and physical, occupational, and speech therapy, reduces the risk of infection and may encourage optimal neurologic development for patients.
If left untreated, prognosis is poor and patients usually die in the first decade of life, often succumbing to infections. Few patients have reached the 2nd and even 3rd decade of life. After HSCT from family or unrelated donors, patients may achieve successful immune reconstitution and are free from infections. Nevertheless, even with HSCT, improvement of neurological deficits is not definite.