Purine Nucleoside Phosphorylase Deficiency
- Author: Alan P Knutsen, MD; Chief Editor: Harumi Jyonouchi, MD more...
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. See the image below.
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. In adenosine deaminase deficiency, adenosine and adenine accumulate in the plasma.[7, 8] 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 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]
Epidemiology
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.
Hirshhorn R, Canotti F. Immunodeficiency due to defects of purine metabolism. In: Ochs HD, Smith CIE, Puck JM, eds. Primary Immunodeficiency Diseases: A Molecular and Genetic Approach. 2nd ed. New York, NY: Oxford University Press, Inc; 2007:169-96.
Hershfield MS, Mitchell BS. Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D. The Metabolic and Molecular Basis of Inherited Disease. New York: McGraw-Hill; 2001:2585-2625.
Arpaia E, Benveniste P, Di Cristofano A, et al. Mitochondrial basis for immune deficiency. Evidence from purine nucleoside phosphorylase-deficient mice. J Exp Med. Jun 19 2000;191(12):2197-208. [Medline].
Bzowska A, Kulikowska E, Shugar D. Purine nucleoside phosphorylases: properties, functions, and clinical aspects. Pharmacol Ther. Dec 2000;88(3):349-425. [Medline].
Markert ML, Hershfield MS, Schiff RI, Buckley RH. Adenosine deaminase and purine nucleoside phosphorylase deficiencies: evaluation of therapeutic interventions in eight patients. J Clin Immunol. Sep 1987;7(5):389-99. [Medline].
Markert ML. Purine nucleoside phosphorylase deficiency. Immunodefic Rev. 1991;3(1):45-81. [Medline].
Hirschhorn R. Overview of biochemical abnormalities and molecular genetics of adenosine deaminase deficiency. Pediatr Res. 1993;33:S35-41.
Hershfield MS. Adenosine deaminase deficiency: clinical expression, molecular basis, and therapy. Semin Hematol. 1998;35:291-298.
Markert ML, Finkel BD, McLaughlin TM, et al. Mutations in purine nucleoside phosphorylase deficiency. Hum Mutat. 1997;9:118-121.
Grunebaum E, Zhang J, Roifman CM. Novel mutations and hot-spots in patients with purine nucleoside phosphorylase deficiency. Nucleosides Nucleotides Nucleic Acids. Oct 2004;23(8-9):1411-5. [Medline].
Buckley RH. Primary immunodeficiency diseases due to defects in lymphocytes. N Engl J Med. Nov 2 2000;343(18):1313-24. [Medline].
Buckley RH, Schiff RI, Schiff SE, et al. Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr. Mar 1997;130(3):378-87. [Medline].
[Best Evidence] Joshi AY, Iyer VN, Hagan JB, St Sauver JL, Boyce TG. Incidence and temporal trends of primary immunodeficiency: a population-based cohort study. Mayo Clin Proc. 2009;84(1):16-22. [Medline].
Hirschhorn R. In vivo reversion to normal of inherited mutations in humans. J Med Genet. 2003;40:721-728.
[Guideline] Bonilla FA, Bernstein IL, Khan DA, et al. Practice parameter for the diagnosis and management of primary immunodeficiency. Ann Allergy Asthma Immunol. May 2005;94(5 Suppl 1):S1-63. [Medline].
Booth C, Hershfield M, Notarangelo L, et al. Management options for adenosine deaminase deficiency; proceedings of the EBMT satellite workshop (Hamburg, March 2006). Clin Immunol. May 2007;123(2):139-47. [Medline].
Broome CB, Graham ML, Saulsbury FT, et al. Correction of purine nucleoside phosphorylase deficiency by transplantation of allogeneic bone marrow from a sibling. J Pediatr. Mar 1996;128(3):373-6. [Medline].
Myers LA, Hershfield MS, Neale WT, et al. Purine nucleoside phosphorylase deficiency (PNP-def) presenting with lymphopenia and developmental delay: successful correction with umbilical cord blood transplantation. J Pediatr. Nov 2004;145(5):710-2. [Medline].
Classen CF, Schulz AS, Sigl-Kraetzig M, et al. Successful HLA-identical bone marrow transplantation in a patient with PNP deficiency using busulfan and fludarabine for conditioning. Bone Marrow Transplant. Jul 2001;28(1):93-6. [Medline].
O'Reilly RJ, Keever C, Kernan NA, et al. HLA nonidentical T cell depleted marrow transplants: a comparison of results in patients treated for leukemia and severe combined immunodeficiency disease. Transplant Proc. Dec 1987;19(6 Suppl 7):55-60. [Medline].
Fischer A, Griscelli C. [Bone marrow graft: graft versus host reaction and rejection]. Nephrologie. 1986;7(3 Suppl):1-4. [Medline].
Hershfield MS. Enzyme replacement therapy of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase (PEG-ADA). Immunodeficiency. 1993;4(1-4):93-7. [Medline].
Toro A, Paiva M, Ackerley C, Grunebaum E. Intracellular delivery of purine nucleoside phosphorylase (PNP) fused to protein transduction domain corrects PNP deficiency in vitro. Cell Immunol. Apr 2006;240(2):107-15. [Medline].
Kohn DB, Hershfield MS, Carbonaro D, et al. T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA- deficient SCID neonates. Nat Med. Jul 1998;4(7):775-80. [Medline].
Aiuti A, Slavin S, Aker M, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science. Jun 28 2002;296(5577):2410-3. [Medline].
Bonagura VR, Marchlewski R, Cox A, Rosenthal DW. Biologic IgG level in primary immunodeficiency disease: the IgG level that protects against recurrent infection. J Allergy Clin Immunol. Jul 2008;122(1):210-2. [Medline].
Durandy A, Wahn V, Petteway S, Gelfand EW. Immunoglobulin replacement therapy in primary antibody deficiency diseases - maximizing success. Int Arch Allergy Immunol. 2005;136:217-229.
Garcia-Lloret M, McGhee S, Chatila TA. Immunoglobulin replacement therapy in children. Immunol Allergy Clin North Am. Nov 2008;28(4):833-49, ix. [Medline].
Hooper JA. Intravenous immunoglobulins: evolution of commercial IVIG preparations. Immunol Allergy Clin North Am. Nov 2008;28(4):765-78, viii. [Medline].
Shah S. Pharmacy considerations for the use of IGIV therapy. Am J Health Syst Pharm. Aug 15 2005;62(16 Suppl 3):S5-11. [Medline].
Lacy CF, Armstrong LL, Goldman MP, Lance LL, eds. Drug Information Handbook. Cleveland, OH: Lexi-Comp, Inc; 2009.
Siegel J. The product: All intravenous immunoglobulins are not equivalent. Pharmacotherapy. Nov 2005;25(11 Pt 2):78S-84S. [Medline].
Routes JM, Grossman WJ, Verbsky J, Laessig RH, Hoffman GL, Brokopp, et al. Statewide newborn screening for severe T-cell lymphopenia. JAMA. Dec 2009;302:2465-2470. [Medline].
Liao P, Toro A, Min W, Lee S, Roifman CM, Grunebaum E. Lentivirus gene therapy for purine nucleoside phosphorylase deficiency. J Gene Med. Dec 2008;10:1282-1293. [Medline].
Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. Jan 2009;360:447-458. [Medline].
| 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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