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Diagnosis, Treatment and Long-Term Follow Up of Patients with ADA Deficiency: a Single-Center Experience

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Abstract

Purpose

We carried out a retrospective analysis of 27 patients with Adenosine Deaminase (ADA) deficiency diagnosed in a single center from 1997 to the 2013, for evaluating whether data regarding types of disease-inducing mutations, biochemical and immunological features as well as clinical outcomes of patients treated with enzyme replacement or transplantation, were comparable to those obtained in multicenter studies.

Methods

The ADA deficiency diagnosis was performed with biochemical, immunological and molecular techniques. Ten patients treated with hematopoietic stem cell transplantation and three in treatment with enzyme replacement were followed up in our center.

Results

Twenty-four different mutations were identified and five were not previously reported. Identical mutations were found among patients from the same Romani ethnic group or from the same geographical region. A more rapid recovery was observed in enzyme replacement treated patients in comparison with those transplanted that, however, showed a continuous and long-lasting improvement both in terms of immune and metabolic recovery.

Conclusion

The data obtained in our single center are comparable with those that have been reported in multicenter surveys.

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References

  1. 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, editors. The metabolic and molecular bases of inherited disease. New York: McGraw-Hill; 2001. p. 2585–625.

    Google Scholar 

  2. Giblett ER, Anderson JE, Cohen F, Pollara B, Meuwissen HJ. Adenosine-deaminase deficiency in two patients with severely impaired cellular immunity. Lancet. 1972;2(7786):1067–9.

    Article  CAS  PubMed  Google Scholar 

  3. Hershfield M. Adenosine deaminase deficiency. In: Pagon RA, Adam MP, Ardinger HH, Bird TD, Dolan CR, Fong CT, Smith RJH, Stephens K, editors. Source: GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993–2014. 2006 Oct 03 [updated 2014 Jun 19].

  4. Seto S, Carrera CJ, Kubota M, Wasson DB, Carson DA. Mechanism of deoxyadenosine and 2-chlorodeoxyadenosine toxicity to nondividing human lymphocytes. J Clin Invest. 1985;75(2):377–83.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  5. Ariga T, Oda N, Sanstisteban I, Arredondo-Vega FX, Shioda M, Ueno H, Terada K, Kobayashi K, Hershfield MS, Sakiyama Y. Molecular basis for paradoxical carriers of adenosine deaminase (ADA) deficiency that show extremely low levels of ADA activity in peripheral blood cells without immunodeficiency. J Immunol. 2001;166(3):1698–702.

    Article  CAS  PubMed  Google Scholar 

  6. Nofech-Mozes Y, Blaser SI, Kobayashi J, Grunebaum E, Roifman CM. Neurologic abnormalities in patients with adenosine deaminase deficiency. Pediatr Neurol. 2007;37(3):218–21.

    Article  PubMed  Google Scholar 

  7. Buckley RH, Schiff RI, Schiff SE, Markert ML, Williams LW, Harville TO, Roberts JL, Puck JM. Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in 108 infants. J Pediatr. 1997;130(3):378–87.

    Article  CAS  PubMed  Google Scholar 

  8. Buckley RH, Schiff SE, Schiff RI, Markert L, Williams LW, Roberts JL, Myers LA, Ward FE. Hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med. 1999;340(7):508–16.

    Article  CAS  PubMed  Google Scholar 

  9. Booth C, Hershfield M, Notarangelo L, Buckley R, Hoenig M, Mahlaoui N, Cavazzana-Calvo M, Aiuti A, Gaspar HB. Management options for adenosine deaminase deficiency; proceedings of the EBMT satellite workshop (Hamburg, March 2006). Clin Immunol. 2007;123(2):139–47 Epub 2007 Feb 14.

    Article  CAS  PubMed  Google Scholar 

  10. Gaspar HB. Bone marrow transplantation and alternatives for adenosine deaminase deficiency. Immunol Allergy Clin N Am. 2010;30(2):221–36.

    Article  Google Scholar 

  11. Aiuti A, Cattaneo F, Galimberti S, Benninghoff U, Cassani B, Callegaro L, Scaramuzza S, Andolfi G, Mirolo M, Brigida I, Tabucchi A, Carlucci F, Eibl M, Aker M, Slavin S, Al-Mousa H, Al Ghonaium A, Ferster A, Duppenthaler A, Notarangelo L, Wintergerst U, Buckley RH, Bregni M, Marktel S, Valsecchi MG, Rossi P, Ciceri F, Miniero R, Bordignon C, Roncarolo MG. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009;360(5):447–58.

    Article  CAS  PubMed  Google Scholar 

  12. Gaspar HB, Aiuti A, Porta F, Candotti F, Hershfield MS, Notarangelo LD. How I treat ADA deficiency. Blood. 2009;114(17):3524–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  13. Antoine C, Müller S, Cant A, Cavazzana-Calvo M, Veys P, Vossen J, Fasth A, Heilmann C, Wulffraat N, Seger R, Blanche S, Friedrich W, Abinun M, Davies G, Bredius R, Schulz A, Landais P, Fischer A. European group for blood and marrow transplantation; European society for immunodeficiency. Long-term survival and transplantation of haemopoietic stem cells for immunodeficiencies: report of the European experience 1968–99. Lancet. 2003;361(9357):553–60.

    Article  PubMed  Google Scholar 

  14. Hassan A, Booth C, Brightwell A, Allwood Z, Veys P, Rao K, Hönig M, Friedrich W, Gennery A, Slatter M, Bredius R, Finocchi A, Cancrini C, Aiuti A, Porta F, Lanfranchi A, Ridella M, Steward C, Filipovich A, Marsh R, Bordon V, Al-Muhsen S, Al-Mousa H, Alsum Z, Al-Dhekri H, Al Ghonaium A, Speckmann C, Fischer A, Mahlaoui N, Nichols KE, Grunebaum E, Al Zahrani D, Roifman CM, Boelens J, Davies EG, Cavazzana-Calvo M, Notarangelo L, Gaspar HB. Inborn errors working party of the European group for blood and marrow transplantation and European society for immunodeficiency. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood. 2012;120(17):3615–24.

    Article  CAS  PubMed  Google Scholar 

  15. Ellis G, Spooner RJ, Goldberg DM. Automated kinetic assays for routine determination of adenosine deaminase and guanase activities of human serum. Clin Chim Acta. 1973;47(1):75–87.

    Article  CAS  PubMed  Google Scholar 

  16. Arredondo-Vega FX, Santisteban I, Richard E, Bali P, Koleilat M, Loubser M, Al-Ghonaium A, Al-Helali M, Hershfield MS. Adenosine deaminase deficiency with mosaicism for a “second-site suppressor” of a splicing mutation: decline in revertant T lymphocytes during enzyme replacement therapy. Blood. 2002;99(3):1005–13.

    Article  CAS  PubMed  Google Scholar 

  17. Chaffee S, Mary A, Stiehm ER, Girault D, Fischer A, Hershfield MS. IgG antibody response to polyethylene glycol-modified adenosine deaminase in patients with adenosine deaminase deficiency. J Clin Invest. 1992;89(5):1643–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Grunebaum E, Mazzolari E, Porta F, Dallera D, Atkinson A, Reid B, Notarangelo LD, Roifman CM. Bone marrow transplantation for severe combined immune deficiency. JAMA. 2006;295(5):508–18.

    Article  CAS  PubMed  Google Scholar 

  19. Mazzolari E, Forino C, Guerci S, Imberti L, Lanfranchi A, Porta F, Notarangelo LD. Long-term immune reconstitution and clinical outcome after stem cell transplantation for severe T-cell immunodeficiency. J Allergy Clin Immunol. 2007;120(4):892–9.

    Article  CAS  PubMed  Google Scholar 

  20. Huenecke S, Behl M, Fadler C, Zimmermann SY, Bochennek K, Tramsen L, Esser R, Klarmann D, Kamper M, Sattler A, von Laer D, Klingebiel T, Lehrnbecher T, Koehl U. Age-matched lymphocyte subpopulation reference values in childhood and adolescence: application of exponential regression analysis. Eur J Haematol. 2008;80(6):532–9.

    Article  PubMed  Google Scholar 

  21. Collins PJ, Hennessy LK, Leibelt CS, Roby RK, Reeder DJ, Foxall PA. Developmental validation of a single-tube amplification of the 13 CODIS STR loci, D2S1338, D19S433, and amelogenin: the AmpFlSTR identifiler PCR amplification kit. J Forensic Sci. 2004;49(6):1265–77.

    Article  CAS  PubMed  Google Scholar 

  22. Zhang L, Lewin SR, Markowitz M, Lin HH, Skulsky E, Karanicolas R, He Y, Jin X, Tuttleton S, Vesanen M, Spiegel H, Kost R, van Lunzen J, Stellbrink HJ, Wolinsky S, Borkowsky W, Palumbo P, Kostrikis LG, Ho DD. Measuring recent thymic emigrants in blood of normal and HIV-1-infected individuals before and after effective therapy. J Exp Med. 1999;190(5):725–32.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  23. Sottini A, Ghidini C, Zanotti C, Chiarini M, Caimi L, Lanfranchi A, Moratto D, Porta F, Imberti L. Simultaneous quantification of recent thymic T-cell and bone marrow B-cell emigrants in patients with primary immunodeficiency undergone to stem cell transplantation. Clin Immunol. 2010;136(2):217–27.

    Article  CAS  PubMed  Google Scholar 

  24. Serana F, Sottini A, Chiarini M, Zanotti C, Ghidini C, Lanfranchi A, Notarangelo LD, Caimi L, Imberti L. The different extent of B and T cell immune reconstitution after hematopoietic stem cell transplantation and enzyme replacement therapies in SCID patients with adenosine deaminase deficiency. J Immunol. 2010;185(12):7713–22.

    Article  CAS  PubMed  Google Scholar 

  25. Santisteban I, Arredondo-Vega FX, Kelly S, Debre M, Fischer A, Pérignon JL, Hilman B, J ED, Dreyfus DH, Gelfand EW, et al. Four new adenosine deaminase mutations, altering a zinc-binding histidine, two conserved alanines, and a 5’ splice site. Hum Mutat. 1995;5(3):243–50.

    Article  CAS  PubMed  Google Scholar 

  26. Arredondo-Vega FX, Santisteban I, Daniels S, Toutain S, Hershfield MS. Adenosine deaminase deficiency: genotype-phenotype correlations based on expressed activity of 29 mutant alleles. Am J Hum Genet. 1998;63(4):1049–59.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Akeson AL, Wiginton DA, Dusing MR, States JC, Hutton JJ. Mutant human adenosine deaminase alleles and their expression by transfection into fibroblasts. J Biol Chem. 1988;263(31):16291–6.

    CAS  PubMed  Google Scholar 

  28. Hirschhorn R Identification of two new missense mutations (R156C and S291L) in two ADA- SCID patients unusual for response to therapy with partial exchange transfusions. Hum Mutat. 1992;1(2):166–8.

    Article  CAS  PubMed  Google Scholar 

  29. Aiuti A, Roncarolo MG. Ten years of gene therapy for primary immune deficiencies. Hematology Am Soc Hematol Educ Program. 2009;2009(1):682–9.

  30. Ferrua F, Brigida I, Aiuti A. Update on gene therapy for adenosine deaminase-deficient severe combined immunodeficiency. Curr Opin Allergy Clin Immunol. 2010;10(6):551–6.

    Article  CAS  PubMed  Google Scholar 

  31. Brigida I, Sauer AV, Ferrua F, Giannelli S, Scaramuzza S, Pistoia V, Castiello MC, Barendregt BH, Cicalese MP, Casiraghi M, Brombin C, Puck J, Müller K, Notarangelo LD, Montin D, Van Montfrans JM, Roncarolo MG, Traggiai E, Van Dongen JJ, Van Der Burg M, Aiuti A. B-cell development and functions and therapeutic options in adenosine deaminase-deficient patients. J Allergy Clin Immunol. 2014;133(3):799–806 e10.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Hershfield MS, Buckley RH, Greenberg ML, Melton AL, Schiff R, Hatem C, Kurtzberg J, Markert ML, Kobayashi RH, Kobayashi AL, et al. Treatment of adenosine deaminase deficiency with polyethylene glycol-modified adenosine deaminase. N Engl J Med. 1987;316(10):589–96.

    Article  CAS  PubMed  Google Scholar 

  33. Levy Y, Hershfield MS, Fernandez-Mejia C, Polmar SH, Scudiery D, Berger M, Sorensen RU. Adenosine deaminase deficiency with late onset of recurrent infections: response to treatment with polyethylene glycol-modified adenosine deaminase. J Pediatr. 1988;113(2):312–7.

    Article  CAS  PubMed  Google Scholar 

  34. Bory C, Boulieu R, Souillet G, Chantin C, Rolland MO, Mathieu M, Hershfield M. Comparison of red cell transfusion and polyethylene glycol-modified adenosine deaminase therapy in an adenosine deaminase-deficient child: measurement of erythrocyte deoxyadenosine triphosphate as a useful tool. Pediatr Res. 1990;28(2):127–30.

    CAS  PubMed  Google Scholar 

  35. Hershfield MS, Chaffee S. PEG-enzyme replacement therapy in adenosine deaminase deficiency. In: Desnick RJ, editor. Treatment of genetic disease. New York: Churchill-Livingstone, Inc.; 1991. p. 169–82.

    Google Scholar 

  36. Hershfield MS. Genotype is an important determinant of phenotype in adenosine deaminase (ADA) deficiency. Curr Opin Immunol. 2003;15:571–7.

    Article  CAS  PubMed  Google Scholar 

  37. Arredondo-Vega FX, Santisteban I, Notarangelo LD, El Dahr J, Buckley R, Roifman C, Conley ME, Hershfield MS. Seven novel mutations in the adenosine deaminase (ADA) gene in patients with severe and delayed onset combined immunodeficiency: G74C, V129M, G140E, R149W, Q199P, 462delG, and E337del. Mutations in brief no. 142. Online. Hum Mutat. 1998;11(6):482.

    Article  Google Scholar 

  38. Li L, Drayna D, Hu D, Hayward A, Gahagan S, Pabst H, Cowan MJ. The gene for severe combined immunodeficiency disease in Athabascan-speaking native Americans is located on chromosome 10p. Am J Hum Genet. 1998;62(1):136–44.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. Markert ML, Norby-Slycord C, Ward FE. A high proportion of ADA point mutations associated with a specific alanine-to-valine substitution. Am J Hum Genet. 1989;45(3):354–61.

    PubMed Central  CAS  PubMed  Google Scholar 

  40. Lainka E, Hershfield MS, Santisteban I, Bali P, Seibt A, Neubert J, Friedrich W, Niehues T. Polyethylene glycol-conjugated adenosine deaminase (ADA) therapy provides temporary immune reconstitution to a child with delayed-onset ADA deficiency. Clin Diagn Lab Immunol. 2005;12(7):861–6.

    PubMed Central  CAS  PubMed  Google Scholar 

  41. Hersfield MS. Biochemistry and immunology of poly (ethylene nglycol) modified adenosine deaminase (PEG-ADA). In: Harris JM, Zalipsky S editors. Poly (ethylene glycol) chemistry and biological applications. Washington, DC: ACS; 1997. p. 145–54.

  42. Speckmann C, Neumann C, Borte S, La Marca G, Sass JO, Wiech E, et al. Delayed-onset adenosine deaminase deficiency: strategies for an early diagnosis. J Allergy Clin Immunol. 2012;130:991–4.

    Article  CAS  PubMed  Google Scholar 

  43. Santisteban I, Arredondo-Vega FX, Kelly S, Mary A, Fischer A, Hummell DS, Lawton A, Sorensen RU, Stiehm ER, Uribe L, et al. Novel splicing, missense, and deletion mutations in seven adenosine deaminase-deficient patients with late/delayed onset of combined immunodeficiency disease. Contribution of genotype to phenotype. J Clin Invest. 1993;92(5):2291–302.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Sauer AV, Brigida I, Carriglio N, Aiuti A. Autoimmune dysregulation and purine metabolism in adenosine deaminase deficiency. Front Immunol. 2012;3:265.

    Article  PubMed Central  PubMed  Google Scholar 

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Conflict of Interest

The authors declare that they have no conflict of interest. MSH and IS receive grant support from Sigma-Tau Pharmaceuticals, the manufacturer of Adagen.

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Authors and Affiliations

  1. Stem Cell Laboratory, Section of Hematology and Blood Coagulation, Children’s Hospital, Spedali Civili of Brescia, Brescia, Italy

    Renata Baffelli, Federica Bolda & Arnalda Lanfranchi

  2. Pediatric Onco-Haematology and BMT Unit, Children’s Hospital, Spedali Civili of Brescia, Brescia, Italy

    Lucia D. Notarangelo & Fulvio Porta

  3. Centro Ricerca Emato-oncologica AIL (CREA), Diagnostics Department, Spedali Civili of Brescia, Brescia, Italy

    Luisa Imberti & Federico Serana

  4. Department of Medicine, Duke University Medical Center, Durham, NC, USA

    Michael S. Hershfield & Ines Santisteban

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  1. Renata Baffelli
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  2. Lucia D. Notarangelo
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  3. Luisa Imberti
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  4. Michael S. Hershfield
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  5. Federico Serana
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  9. Arnalda Lanfranchi
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Correspondence to Arnalda Lanfranchi.

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Baffelli, R., Notarangelo, L.D., Imberti, L. et al. Diagnosis, Treatment and Long-Term Follow Up of Patients with ADA Deficiency: a Single-Center Experience. J Clin Immunol 35, 624–637 (2015). https://doi.org/10.1007/s10875-015-0191-z

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  • DOI: https://doi.org/10.1007/s10875-015-0191-z

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