eMedicine Specialties > Pediatrics: General Medicine > Allergy & Immunology

Purine Nucleoside Phosphorylase Deficiency

Author: Alan P Knutsen, MD, Professor of Pediatrics, Director of Pediatric Allergy and Immunology, Director of Pediatric Clinical Immunology Laboratory, Department of Pathology, St Louis University Health Sciences Center
Contributor Information and Disclosures

Updated: May 21, 2009

Introduction

Background

Two genetic defects of the purine salvage pathway account for two immunodeficiencies that result in severe combined immunodeficiency (SCID).^1,2 One disorder is adenosine deaminase (ADA) deficiency, which is Online Mendelian Inheritance in Man (OMIM) subject number 102700, and the other is purine nucleoside phosphorylase (PNP) deficiency, which is OMIM subject number 164050. 

Adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency are autosomal recessive disorders. Adenosine deaminase and purine nucleoside phosphorylase are ubiquitous "housekeeping genes." In both disorders, the enzyme deficiencies result in accumulation of toxic metabolites, especially in lymphocytes. In adenosine deaminase deficiency, the toxic metabolites block T-cell, B-cell, and natural killer (NK)-cell development; whereas in purine nucleoside phosphorylase deficiency, the metabolites are toxic to T-cell development.

In addition, in both adenosine deaminase and purine nucleoside phosphorylase deficiencies, neurodevelopmental delay occurs. This is especially prevalent in purine nucleoside phosphorylase deficiency with neurologic symptoms, including mental retardation and muscle spasticity, reported in 67% of patients. In addition, purine nucleoside phosphorylase deficiency is associated with increased risk of autoimmune disorders, such as autoimmune hemolytic anemia, immune thrombocytopenia, neutropenia, thyroiditis, and lupus.

Adenosine deaminase deficiency results in absence of T cells, B cells, and NK cells, resulting in a form of SCID associated with marked lymphopenia. Purine nucleoside phosphorylase deficiency causes decreased numbers of T cells and lymphopenia. Serum immunoglobulin (Ig) levels are normal to near-normal, but antibodies are deficient.

Pathophysiology

Purine nucleoside phosphorylase is an enzyme in the purine salvage pathway that metabolizes inosine and guanosine to hypoxanthine.^3,4,5,6 In the preceding step of the pathway, adenosine deaminase metabolizes adenosine to inosine. Adenosine deaminase 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 cells and B cells.

In purine nucleoside phosphorylase deficiency, similar changes occur, resulting 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 adenosine deaminase and purine nucleoside phosphorylase 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 purine nucleoside phosphorylase deficiency, Arpaia et al reported increased in vivo apoptosis of T cells and increased in vitro sensitivity to gamma irradiation in a murine model.³ The immune deficiency in purine nucleoside phosphorylase 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 adenosine deaminase deficiency, destruction of resting T cells and B cells is increased. In comparison, purine nucleoside phosphorylase 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.¹ Purine nucleoside phosphorylase 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 adenosine deaminase are necessary for competent immunity, some patients with ADA mutations may still have 8-42% adenosine deaminase activity and no profound immunodeficiency.^1,2

Frequency

United States

Purine nucleoside phosphorylase deficiency is rare; it has been reported in approximately 30 families.^6,9,10 Purine nucleoside phosphorylase deficiency accounts for approximately 4% of all cases of SCID.⁶
 
Adenosine deaminase deficiency accounts for approximately 20% of all cases of SCID.^11,12

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. Combined immunodeficiency (CID) accounts for 11-13% of all primary immunodeficiency disorders. A recent study noted that the incidence of primary immunodeficiency disorders markedly increased from 1976-2006.¹³

Mortality/Morbidity

Patients with purine nucleoside phosphorylase 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 purine nucleoside phosphorylase deficiency. Neurologic symptoms, including mental retardation and muscle spasticity, are major comorbid conditions that affect 67% of patients with purine nucleoside phosphorylase 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

Purine nucleoside phosphorylase immunodeficiency and adenosine deaminase immunodeficiency are autosomal recessive disorders with equal incidence in boys and girls.

Age

Although symptoms typically appear in the first year of life in patients with purine nucleoside phosphorylase deficiency, gradual deterioration of the T-cell immune system may delay the onset of symptoms until the second year of life.

Clinical

History

Most patients with purine nucleoside phosphorylase (PNP) deficiency have a history of recurrent viral, bacterial, fungal, mycobacterial, and protozoal infections, similar to patients with severe combined immunodeficiency (SCID).^1,2 Oral candidiasis that is recalcitrant to therapy occurs in approximately 85% of patients with severe T-cell immunodeficiency. In addition, the presenting infections are often those caused by opportunistic microorganisms, such as Pneumocystis jiroveci pneumonia.

Neurologic problems are commonly associated with purine nucleoside phosphorylase and adenosine deaminase (ADA) deficiencies and have therapeutic implications. More than 50% of patients with purine nucleoside phosphorylase deficiency have neurologic impairments that may predate the onset of infections. Neurologic problems include developmental delay, hypertonia, spasticity, tremors, ataxia, retarded motor development, behavioral difficulties, and varying degrees of mental retardation.⁶ Patients with adenosine deaminase deficiency may also have neurologic problems, principally neurodevelopmental delays. Of importance, polyethylene glycol (PEG) adenosine deaminase therapy does not correct the neurodevelopmental problems in adenosine deaminase deficiency, although immune reconstitution does occur. Likewise, bone marrow transplantation does not correct neurological deficits in purine nucleoside phosphorylase or adenosine deaminase deficiencies.

Autoimmune disorders are also frequent in purine nucleoside phosphorylase immunodeficiency.⁶ These include autoimmune hemolytic anemia (AHA), idiopathic thrombocytopenia (ITP), autoimmune neutropenia, lupus, thyroiditis, and central nervous vasculitis. 

Lymphoma and lymphosarcoma has also been reported in children with purine nucleoside phosphorylase immunodeficiency.

• Purine nucleoside phosphorylase immunodeficiency
  • Patients with purine nucleoside phosphorylase deficiency may have recurrent sinopulmonary infections that may result in a delay in diagnosis until late childhood.
  • Patients with purine nucleoside phosphorylase deficiency, similar to patients with serious T-cell immune deficiency, are susceptible to herpes infections (eg, varicella).
  • Patients with purine nucleoside phosphorylase deficiency are also susceptible to recurrent urinary tract infections.
• Adenosine deaminase immunodeficiency
  • Infections typically appear in infancy. However, T-cell function can fluctuate and might not be completely absent. Therefore, a spectrum of T-cell immune deficiency is reported in patients with adenosine deaminase deficiency.
  • Major clinical phenotypes of adenosine deaminase deficiency have been described, as follows:
    • Neonatal or infantile onset - Indistinguishable from other forms of SCID; bony abnormalities in 50%
    • Delayed - Onset at age 0-2 years; retention of immunoglobulin (Ig) with later attrition, susceptibility to infection similar to that of adenosine deaminase SCID
    • Late onset -  Onset at age 3-15 years; may present with recurrent bacterial sinopulmonary infections typical for antibody immunodeficiency, lymphopenia (measure adenosine deaminase and purine nucleoside phosphorylase activity), hyper-IgE, eosinophilia, autoimmunity; may be misdiagnosed as common variable immunodeficiency (CVID) or IgG2-subclass deficiency/specific antibody deficiency
    • Adult onset - Same as late onset, but in adolescents or young adults, plus persistent warts, recurrent herpes zoster, idiopathic thrombocytopenic purpura, lymphopenia; may be misdiagnosed as CVID or IgG2-subclass deficiency/specific antibody deficiency
    • Somatic mosaicism (de novo or revertant mutations) - May show improvement over time without treatment
  • Both partial adenosine deaminase deficiency and somatic mosaicism have no confirmed immunodeficiency. Some individuals may have very low levels of adenosine deaminase activity in lymphocytes but retain 55-80% normal adenosine deaminase activity in RBCs. These children were healthy in childhood.  In addition, revertant mutations of inherited ADA gene mutations have been described.¹⁴

Physical

Physical examination reveals a paucity of peripheral lymphoid tissue, such as lymph nodes, tonsillar tissue, and adenoids. The liver and spleen are usually normal in size but can be enlarged in patients with accompanying hemolytic anemia or lymphoma. In neonates, the thymic shadow is typically small on chest radiography. Neurologic symptoms, consisting of developmental delay, hypertonia, spasticity, and tremors, may be present. Patients may fail to thrive.

Causes

Purine nucleoside phosphorylase deficiency is a genetic disorder caused by a deficiency of the enzyme purine nucleoside phosphorylase. The PNP gene has been localized to band 14q13. Missense mutations have been identified in some patients. The purine nucleoside phosphorylase protein is a trimer with a molecular weight of 84-94 kDa, with the highest levels in lymphoid tissue. The mechanism by which purine nucleoside phosphorylase deficiency causes neurologic disease is unknown.

• Search for CME/CE on This Topic »

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• Severe Combined Immunodeficiency (Allergy and Immunology)