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). [2, 3] 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.
Live-attenuated immunizations should be avoided as they may result in infection. Rotovirus immunizations resulting in infection has been reported in patients with SCID. Varivax immunization has resulted in disseminated varicella. BCG immunization may cause pulmonary or disseminated infection. [12] Progressive multifocal leukoencephalopathy due to polyomavirus infection has been reported. [13]
Neurologic problems are commonly associated with PNP and adenosine deaminase (ADA) deficiencies and have therapeutic implications. More than 50% of patients with PNP 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. [7] Patients with ADA deficiency may also have neurologic problems, principally neurodevelopmental delays. Of importance, polyethylene glycol (PEG) ADA therapy does not correct the neurodevelopmental problems in ADA deficiency, although immune reconstitution does occur. Likewise, bone marrow transplantation does not correct neurological deficits in PNP or ADA deficiencies.
Autoimmune disorders are also frequent in PNP deficiency. [7] 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 PNP immunodeficiency.
Purine nucleoside phosphorylase immunodeficiency
Patients with PNP deficiency may have recurrent sinopulmonary infections that may result in a delay in diagnosis until late childhood.
Patients with PNP 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 ADA deficiency. [14]
Live-attenuated immunizations should be avoided as they may result in infection. Rotovirus immunizations resulting in infection has been reported in patients with SCID. Varivax immunization has resulted in disseminated varicella. BCG immunization may cause pulmonary or disseminated infection. [12] Progressive multifocal leukoencephalopathy due to polyomavirus infection has been reported. [13]
Major clinical phenotypes of ADA deficiency have been described, as follows:
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Neonatal or infantile onset – This is indistinguishable from other forms of SCID; bony abnormalities are reported in 50% of patients. In ADA-deficient SCID, there are a number of metaphyseal changes that can be identified radiologically. [15] These include concavity and flaring of the anterior rib costochondral functions, squaring of the ilia, abnormal posterior costovertebral junctions, platyspondyly, growth arrest lines, trabecular paucity, and overall mild shortening of the extremities and scapular spurring. Grunebaum et al [16] reported pulmonary alveolar proteinosis (PAP) in patients with ADA deficiency. Interestingly, PAP was reversed with polyethylene glycol–ADA therapy.
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Delayed - Onset at age 0-2 years; retention of immunoglobulin (Ig) with later attrition, susceptibility to infection similar to that of ADA SCID
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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
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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
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Somatic mosaicism (de novo or revertant mutations) - May show improvement over time without treatment
Both partial ADA deficiency and somatic mosaicism have no confirmed immunodeficiency. Some individuals may have very low levels of ADA activity in lymphocytes but retain 55-80% normal ADA activity in RBCs. These children were healthy in childhood. In addition, revertant mutations of inherited ADA gene mutations have been described. [17]
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
PNP 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 PNP protein is a trimer with a molecular weight of 84-94 kDa, with the highest levels in lymphoid tissue. The mechanism by which PNP deficiency causes neurologic disease is unknown.
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Biochemical pathway of purine metabolism. AMP = adenosine monophosphate, APRT = adenine phosphoribosyltransferase, GMP = guanosine monophosphate, HGPRT = hypoxanthine-guanine phosphoribosyltransferase, IMP = inosine monophosphate, NP = nucleoside phosphorylase, PPriboseP = 5-phosphorylribose-1-pyrophosphate.
Tables
Study |
Infantile Onset |
Late Onset |
Adult Onset |
Lymphopenia |
Markedly decreased |
Decreased |
Decreased |
CD3+ cells |
Absent or trace |
Markedly reduced |
Markedly reduced |
CD4/CD8 ratio |
Too few to test |
< 1 |
< 1 |
Phytohemagglutinin response |
Absent |
Reduced |
Reduced |
Antigen response |
Absent |
Trace |
Trace |
Mixed lymphocyte culture response |
Reduced |
... |
... |
Ig response |
Absent |
Low to absent |
Normal (low IgG2) |
IgE |
Low |
Elevated |
Elevated |
Antibody response |
Absent |
Absent to low |
Low to polysaccharides antigens |
Eosinophilia |
Rare |
Common |
Common |
Infections |
Predominantly viral, fungal, opportunistic, bacterial |
Bacterial sinopulmonary |
Bacterial sinopulmonary, varicella-zoster, herpes simplex, candidal |
Brand (Manufacturer) |
Manufacturing Process |
pH |
Additives* |
Parenteral Form and Final Concentration |
IgA Content (mcg/mL) |
Carimune NF (CSL Behring) |
Kistler-Nitschmann fractionation; pH 4, nanofiltration |
6.4-6.8 |
6% solution: 10% sucrose < 20 mg NaCl/g protein |
Lyophilized powder 3%, 6%, 9%, 12% |
Trace |
Flebogamma (Grifols USA) |
Cohn-Oncley fractionation, polyethyline glycol (PEG) precipitation, ion-exchange chromatography, pasteurization |
5.1-6 |
Sucrose-free, contains 5% D-sorbitol |
Liquid 5% |
< 50 |
Gamunex (Talecris Biotherapeutics) |
Cohn-Oncley fractionation, caprylate-chromatography purification, cloth and depth filtration, low pH incubation |
4-4.5 |
Contains no sugar, contains glycine |
Liquid 10% |
46 |
Iveegam EN (Baxter Bioscience) |
Cohn-Oncley fraction II/III; ultrafiltration; pasteurization |
6.4-7.2 |
5% solution: 5% glucose, 0.3% NaCl |
Lyophilized powder 5% |
< 10 |
Gammagard S/D, Polygam S/D (Baxter Bioscience for the American Red Cross) |
Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation |
6.4-7.2 |
5% solution: 0.3% albumin, 2.25% glycine, 2% glucose |
Lyophylized powder 5%, 10% |
< 1.6 (5% solution) |
Gammagard Liquid 10% (Baxter Bioscience) |
Cohn-Oncley cold ethanol fractionation, cation and anion exchange chromatography, solvent detergent treated, nanofiltration, low pH incubation |
4.6-5.1 |
0.25M glycine |
Ready-for-use Liquid 10% |
37 |
Octagam (Octapharma USA) |
Cohn-Oncley fraction II/III; ultrafiltration; low pH incubation; S/D treatment pasteurization |
5.1-6 |
10% maltose |
Liquid 5% |
200 |
Panglobulin (Swiss Red Cross for the American Red Cross) |
Kistler-Nitschmann fractionation; pH 4, trace pepsin, nanofiltration |
6.6 |
Per gram of IgG: 1.67 g sucrose, < 20 mg NaCl |
Lyophilized powder 3%, 6%, 9%, 12% |
720 |
Privigen Liquid 10% (CSL Behring) |
Cold ethanol fractionation, octanoic acid fractionation, and anion exchange chromatography; pH 4 incubation and depth filtration |
4.6-5 |
L-proline (~250 mmol/L) as stabilizer; trace sodium; does not contain carbohydrate stabilizers |
Ready-for use liquid 10% |
< 25 |
*IVIG products containing sucrose are more often associated with renal dysfunction, acute renal failure, and osmotic nephrosis, particularly with preexisting risk factors (eg, history of renal insufficiency, diabetes mellitus, age >65 y, dehydration, sepsis, paraproteinemia, nephrotoxic drugs). |
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