Official reprint from UpToDate®
www.uptodate.com ©2016 UpToDate®

Adenosine deaminase deficiency: Pathogenesis, clinical manifestations, and diagnosis

Arye Rubinstein, MD
Section Editor
E Richard Stiehm, MD
Deputy Editor
Elizabeth TePas, MD, MS


Adenosine deaminase (ADA) deficiency (MIM 102700) was the first immunodeficiency in which the specific molecular defect was described. This autosomal recessive genetic disorder typically leads to a severe combined immunodeficiency (SCID) with dysfunction of T, B, and natural killer (NK) cells (T-B-NK- SCID) that presents in the first few months of life (table 1). However, there are also a few patients with a later onset and relatively milder disease. The wide spectrum of the ADA deficiency phenotype is largely related to the variability in genetic mutations.

The pathogenesis, clinical manifestations, and diagnosis of ADA deficiency are presented in this topic review. The treatment of ADA deficiency is discussed separately, as is the related combined immunodeficiency disorder, purine nucleoside phosphorylase deficiency. (See "Adenosine deaminase deficiency: Treatment" and "Purine nucleoside phosphorylase deficiency".)

An overview of SCID and detailed discussions on other SCID syndromes and combined immunodeficiencies are also covered separately. (See "Severe combined immunodeficiency (SCID): An overview" and "Severe combined immunodeficiency (SCID): Specific defects" and "Combined immunodeficiencies".)


ADA deficiency has an overall incidence of 1 in 200,000 livebirths. It accounts for approximately one-third of all cases of autosomal recessive severe combined immunodeficiency (SCID) and approximately 15 percent of all cases of SCID [1,2].


ADA deficiency is caused by mutations in the ADA1 gene at 20q13.11 (MIM 608958) [3-6]. ADA is an ubiquitous enzyme found in all cells, including red and white blood cells, and in the serum. It catalyzes the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine, which are converted to waste products and excreted. In the absence of functional ADA, there is an intracellular accumulation of adenosine and deoxyadenosine. The replicative activity of the cell dictates the level of sensitivity to these toxic metabolites.


Subscribers log in here

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information or to purchase a personal subscription, click below on the option that best describes you:
Literature review current through: Nov 2016. | This topic last updated: Mon Nov 07 00:00:00 GMT+00:00 2016.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2016 UpToDate, Inc.
  1. Buckley RH, Schiff RI, Schiff SE, et al. Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants. J Pediatr 1997; 130:378.
  2. Hershfield MS. Genotype is an important determinant of phenotype in adenosine deaminase deficiency. Curr Opin Immunol 2003; 15:571.
  3. Wiginton DA, Adrian GS, Friedman RL, et al. Cloning of cDNA sequences of human adenosine deaminase. Proc Natl Acad Sci U S A 1983; 80:7481.
  4. Wiginton DA, Kaplan DJ, States JC, et al. Complete sequence and structure of the gene for human adenosine deaminase. Biochemistry 1986; 25:8234.
  5. Jhanwar SC, Berkvens TM, Breukel C, et al. Localization of human adenosine deaminase (ADA) gene sequences to the q12----q13.11 region of chromosome 20 by in situ hybridization. Cytogenet Cell Genet 1989; 50:168.
  6. 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; 45:354.
  7. Hershfield MS, Kredich NM, Ownby DR, et al. In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients. J Clin Invest 1979; 63:807.
  8. Middleton's allergy: Principles and practice, 6th ed, Adkinson NF, Yunginger JW, Busse WW, et al (Eds), Mosby, St. Louis 2003.
  9. Rubinstein A, Hirschhorn R, Sicklick M, Murphy RA. In vivo and in vitro effects of thymosin and adenosine deaminase on adenosine-deaminase-deficient lymphocytes. N Engl J Med 1979; 300:387.
  10. Joachims ML, Marble PA, Laurent AB, et al. Restoration of adenosine deaminase-deficient human thymocyte development in vitro by inhibition of deoxynucleoside kinases. J Immunol 2008; 181:8153.
  11. Apasov SG, Blackburn MR, Kellems RE, et al. Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling. J Clin Invest 2001; 108:131.
  12. Cassani B, Mirolo M, Cattaneo F, et al. Altered intracellular and extracellular signaling leads to impaired T-cell functions in ADA-SCID patients. Blood 2008; 111:4209.
  13. Sokolic R, Maric I, Kesserwan C, et al. Myeloid dysplasia and bone marrow hypocellularity in adenosine deaminase-deficient severe combined immune deficiency. Blood 2011; 118:2688.
  14. Navon Elkan P, Pierce SB, Segel R, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med 2014; 370:921.
  15. Zhou Q, Yang D, Ombrello AK, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med 2014; 370:911.
  16. Nanthapisal S, Murphy C, Omoyinmi E, et al. Deficiency of Adenosine Deaminase Type 2: A Description of Phenotype and Genotype in Fifteen Cases. Arthritis Rheumatol 2016; 68:2314.
  17. Van Montfrans JM, Hartman EA, Braun KP, et al. Phenotypic variability in patients with ADA2 deficiency due to identical homozygous R169Q mutations. Rheumatology (Oxford) 2016; 55:902.
  18. Ben-Ami T, Revel-Vilk S, Brooks R, et al. Extending the Clinical Phenotype of Adenosine Deaminase 2 Deficiency. J Pediatr 2016; 177:316.
  19. Bollinger ME, Arredondo-Vega FX, Santisteban I, et al. Brief report: hepatic dysfunction as a complication of adenosine deaminase deficiency. N Engl J Med 1996; 334:1367.
  20. Morgan G, Levinsky RJ, Hugh-Jones K, et al. Heterogeneity of biochemical, clinical and immunological parameters in severe combined immunodeficiency due to adenosine deaminase deficiency. Clin Exp Immunol 1987; 70:491.
  21. Heyderman RS, Morgan G, Levinsky RJ, Strobel S. Successful bone marrow transplantation and treatment of BCG infection in two patients with severe combined immunodeficiency. Eur J Pediatr 1991; 150:477.
  22. Hirschhorn R, Tzall S, Ellenbogen A, Orkin SH. Identification of a point mutation resulting in a heat-labile adenosine deaminase (ADA) in two unrelated children with partial ADA deficiency. J Clin Invest 1989; 83:497.
  23. Hirschhorn R, Tzall S, Ellenbogen A. Hot spot mutations in adenosine deaminase deficiency. Proc Natl Acad Sci U S A 1990; 87:6171.
  24. Artac H, Göktürk B, Bozdemir SE, et al. Late-onset adenosine deaminase deficiency presenting with Heck's disease. Eur J Pediatr 2010; 169:1033.
  25. Shovlin CL, Simmonds HA, Fairbanks LD, et al. Adult onset immunodeficiency caused by inherited adenosine deaminase deficiency. J Immunol 1994; 153:2331.
  26. Ozsahin H, Arredondo-Vega FX, Santisteban I, et al. Adenosine deaminase deficiency in adults. Blood 1997; 89:2849.
  27. Hönig M, Albert MH, Schulz A, et al. Patients with adenosine deaminase deficiency surviving after hematopoietic stem cell transplantation are at high risk of CNS complications. Blood 2007; 109:3595.
  28. Titman P, Pink E, Skucek E, et al. Cognitive and behavioral abnormalities in children after hematopoietic stem cell transplantation for severe congenital immunodeficiencies. Blood 2008; 112:3907.
  29. Albuquerque W, Gaspar HB. Bilateral sensorineural deafness in adenosine deaminase-deficient severe combined immunodeficiency. J Pediatr 2004; 144:278.
  30. Gaspar HB. Bone marrow transplantation and alternatives for adenosine deaminase deficiency. Immunol Allergy Clin North Am 2010; 30:221.
  31. Husain M, Grunebaum E, Naqvi A, et al. Burkitt's lymphoma in a patient with adenosine deaminase deficiency-severe combined immunodeficiency treated with polyethylene glycol-adenosine deaminase. J Pediatr 2007; 151:93.
  32. Rubinstein A, Albert Einstein College of Medicine, 2004, personal communication.
  33. Kesserwan C, Sokolic R, Cowen EW, et al. Multicentric dermatofibrosarcoma protuberans in patients with adenosine deaminase-deficient severe combined immune deficiency. J Allergy Clin Immunol 2012; 129:762.
  34. Grunebaum E, Cutz E, Roifman CM. Pulmonary alveolar proteinosis in patients with adenosine deaminase deficiency. J Allergy Clin Immunol 2012; 129:1588.
  35. Hirschhorn R, Yang DR, Israni A, et al. Somatic mosaicism for a newly identified splice-site mutation in a patient with adenosine deaminase-deficient immunodeficiency and spontaneous clinical recovery. Am J Hum Genet 1994; 55:59.
  36. Hirschhorn R, Yang DR, Puck JM, et al. Spontaneous in vivo reversion to normal of an inherited mutation in a patient with adenosine deaminase deficiency. Nat Genet 1996; 13:290.
  37. Wada T, Candotti F. Somatic mosaicism in primary immune deficiencies. Curr Opin Allergy Clin Immunol 2008; 8:510.
  38. Cohen A, Hirschhorn R, Horowitz SD, et al. Deoxyadenosine triphosphate as a potentially toxic metabolite in adenosine deaminase deficiency. Proc Natl Acad Sci U S A 1978; 75:472.
  39. Donofrio J, Coleman MS, Hutton JJ, et al. Overproduction of adenine deoxynucleosides and deoxynucletides in adenosine deaminase deficiency with severe combined immunodeficiency disease. J Clin Invest 1978; 62:884.
  40. Simmonds HA, Sahota A, Potter CF, Cameron JS. Purine metabolism and immunodeficiency: urinary purine excretion as a diagnostic screening test in adenosine deaminase and purine nucleoside phosphorylase deficiency. Clin Sci Mol Med 1978; 54:579.
  41. Wolfson JJ, Cross VF. The radiologic findings in 49 patients with combined immunodeficiency. In: Combined immunodeficiency diseases and adenosine deaminase deficiency: A molecular defect, Meuwissen HJ, Pickering RJ, Pollara B, Porter IH (Eds), Academic Press, New York 1975. p.225.
  42. Pérignon JL, Durandy A, Peter MO, et al. Early prenatal diagnosis of inherited severe immunodeficiencies linked to enzyme deficiencies. J Pediatr 1987; 111:595.
  43. Hershfield M. Adenosine deaminase deficiency. In: Pagon RA, Bird TD, Dolan CR, Stephens K, editors. GeneReviews [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2006 Oct 03 [updated 2009 Jul 14]. http://www.ncbi.nlm.nih.gov/pubmed?term=20301656 (Accessed on February 15, 2011).
  44. Routes JM, Grossman WJ, Verbsky J, et al. Statewide newborn screening for severe T-cell lymphopenia. JAMA 2009; 302:2465.
  45. Beth Vogel, New York State Department of Health, January 2011.
  46. Morinishi Y, Imai K, Nakagawa N, et al. Identification of severe combined immunodeficiency by T-cell receptor excision circles quantification using neonatal guthrie cards. J Pediatr 2009; 155:829.