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Orphanet Journal of Rare Diseases
Published in: Orphanet Journal of Rare Diseases 1/2018

Open Access 01-12-2018 | Review

Adenosine deaminase deficiency: a review

Authors: Aisling M. Flinn, Andrew R. Gennery

Published in: Orphanet Journal of Rare Diseases | Issue 1/2018

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Abstract

Adenosine deaminase (ADA) deficiency leads to an accumulation of toxic purine degradation by-products, most potently affecting lymphocytes, leading to adenosine deaminase-deficient severe combined immunodeficiency. Whilst most notable affects are on lymphocytes, other manifestations include skeletal abnormalities, neurodevelopmental affects and pulmonary manifestations associated with pulmonary-alveolar proteinosis. Affected patients present in early infancy, usually with persistent infection, or with pulmonary insufficiency. Three treatment options are currently available. Initial treatment with enzyme replacement therapy may alleviate acute symptoms and enable partial immunological reconstitution, but treatment is life-long, immune reconstitution is incomplete, and the reconstituted immune system may nullify the effects of the enzyme replacement. Hematopoietic stem cell transplant has long been established as the treatment of choice, particularly where a matched sibling or well matched unrelated donor is available. More recently, the use of gene addition techniques to correct the genetic defect in autologous haematopoietic stem cells treatment has demonstrated immunological and clinical efficacy. This article reviews the biology, clinical presentation, diagnosis and treatment of ADA-deficiency.
Literature
1.
Gaspar HB. Bone marrow transplantation and alternatives for adenosine deaminase deficiency. Immunol Allergy Clin N Am. 2010;30(2):221–36.CrossRef
2.
3.
Kameoka J, Tanaka T, Nojima Y, Schlossman SF, Morimoto C. Direct association of adenosine deaminase with a T cell activation antigen, CD26. Science. 1993;261(5120):466–9.CrossRefPubMed
4.
Benveniste P, Zhu W, Cohen A. Interference with thymocyte differentiation by an inhibitor of S-adenosylhomocysteine hydrolase. J Immunol. 1995;155(2):536–44.PubMed
5.
Blackburn MR, Kellems RE. Adenosine deaminase deficiency: metabolic basis of immune deficiency and pulmonary inflammation. Adv Immunol. 2005;86:1–41.CrossRefPubMed
6.
Sitkovsky MV, Lukashev D, Apasov S, et al. Physiological control of immune response and inflammatory tissue damage by hypoxia-inducible factors and adenosine A2A receptors. Annu Rev Immunol. 2004;22:657–82.CrossRefPubMed
7.
8.
Hershfield M. Adenosine Deaminase Deficiency. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews(R). Seattle (WA): University of Washington, Seattle, University of Washington, Seattle: GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved; 1993.
9.
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.CrossRefPubMedPubMedCentral
10.
Hirschhorn R, Martiniuk F, Rosen FS. Adenosine deaminase activity in normal tissues and tissues from a child with severe combined immunodeficiency and adenosine deaminase deficiency. Clin Immunol Immunopathol. 1978;9(3):287–92.CrossRefPubMed
11.
Apasov SG, Blackburn MR, Kellems RE, Smith PT, Sitkovsky MV. Adenosine deaminase deficiency increases thymic apoptosis and causes defective T cell receptor signaling. J Clin Invest. 2001;108(1):131–41.CrossRefPubMedPubMedCentral
12.
Aldrich MB, Chen W, Blackburn MR, Martinez-Valdez H, Datta SK, Kellems RE. Impaired germinal center maturation in adenosine deaminase deficiency. J Immunol. 2003;171(10):5562–70.CrossRefPubMed
13.
Gangi-Peterson L, Sorscher DH, Reynolds JW, Kepler TB, Mitchell BS. Nucleotide pool imbalance and adenosine deaminase deficiency induce alterations of N-region insertions during V(D)J recombination. J Clin Invest. 1999;103(6):833–41.CrossRefPubMedPubMedCentral
14.
Rogers MH, Lwin R, Fairbanks L, Gerritsen B, Gaspar HB. Cognitive and behavioral abnormalities in adenosine deaminase deficient severe combined immunodeficiency. J Pediatr. 2001;139(1):44–50.CrossRefPubMed
15.
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(9):3907–13.CrossRefPubMed
16.
Tanaka C, Hara T, Suzaki I, Maegaki Y, Takeshita K. Sensorineural deafness in siblings with adenosine deaminase deficiency. Brain and Development. 1996;18(4):304–6.CrossRefPubMed
17.
Albuquerque W, Gaspar HB. Bilateral sensorineural deafness in adenosine deaminase-deficient severe combined immunodeficiency. J Pediatr. 2004;144(2):278–80.CrossRefPubMed
18.
Chunn JL, Molina JG, Mi T, Xia Y, Kellems RE, Blackburn MR. Adenosine-dependent pulmonary fibrosis in adenosine deaminase-deficient mice. J Immunol. 2005;175(3):1937–46.CrossRefPubMed
19.
Booth C, Algar VE, Xu-Bayford J, Fairbanks L, Owens C, Gaspar HB. Non-infectious lung disease in patients with adenosine deaminase deficient severe combined immunodeficiency. J Clin Immunol. 2012;32(3):449–53.CrossRefPubMed
20.
Grunebaum E, Cutz E, Roifman CM. Pulmonary alveolar proteinosis in patients with adenosine deaminase deficiency. J Allergy Clin Immunol. 2012;129(6):1588–93.CrossRefPubMed
21.
Manson D, Diamond L, Oudjhane K, Hussain FB, Roifman C, Grunebaum E. Characteristic scapular and rib changes on chest radiographs of children with ADA-deficiency SCIDS in the first year of life. Pediatr Radiol. 2013;43(5):589–92.CrossRefPubMed
22.
Ratech H, Greco MA, Gallo G, Rimoin DL, Kamino H, Hirschhorn R. Pathologic findings in adenosine deaminase-deficient severe combined immunodeficiency. I. Kidney, adrenal, and chondro-osseous tissue alterations. Am J Pathol. 1985;120(1):157–69.PubMedPubMedCentral
23.
Sauer AV, Mrak E, Hernandez RJ, et al. ADA-deficient SCID is associated with a specific microenvironment and bone phenotype characterized by RANKL/OPG imbalance and osteoblast insufficiency. Blood. 2009;114(15):3216–26.CrossRefPubMed
24.
Kaitila I, Rimoin DL, Cedarbaum SD, Stiehm ER, Lachman RS. Chondroosseous histopathology in adenosine deaminase deficient combined immunodeficiency disease. Birth Defects Orig Artic Ser. 1976;12(6):115–21.PubMed
25.
Wakamiya M, Blackburn MR, Jurecic R, et al. Disruption of the adenosine deaminase gene causes hepatocellular impairment and perinatal lethality in mice. Proc Natl Acad Sci U S A. 1995;92(9):3673–7.CrossRefPubMedPubMedCentral
26.
Kuhl JS, Schwarz K, Munch A, et al. Hyperbilirubinemia and rapid fatal hepatic failure in severe combined immunodeficiency caused by adenosine deaminase deficiency (ADA-SCID). Klin Padiatr. 2011;223(2):85–9.CrossRefPubMed
27.
Bollinger ME, Arredondo-Vega FX, Santisteban I, Schwarz K, Hershfield MS, Lederman HM. Brief report: Hepatic dysfunction as a complication of adenosine deaminase deficiency. N Engl J Med. 1996;334(21):1367–71.CrossRefPubMed
28.
Nikolajeva O, Worth A, Hague R, et al. Adenosine deaminase deficient severe combined immunodeficiency presenting as atypical haemolytic uraemic syndrome. J Clin Immunol. 2015;35(4):366–72.CrossRefPubMed
29.
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(3):762–769.e761.CrossRefPubMed
30.
Santisteban I, Arredondo-Vega FX, Kelly S, 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.CrossRefPubMedPubMedCentral
31.
Shovlin CL, Hughes JM, Simmonds HA, et al. Adult presentation of adenosine deaminase deficiency. Lancet. 1993;341(8858):1471.CrossRefPubMed
32.
Artac H, Gokturk B, Bozdemir SE, et al. Late-onset adenosine deaminase deficiency presenting with Heck's disease. Eur J Pediatr. 2010;169(8):1033–6.CrossRefPubMed
33.
Hirschhorn R, Martiniuk F, Roegner-Maniscalco V, Ellenbogen A, Perignon JL, Jenkins T. Genetic heterogeneity in partial adenosine deaminase deficiency. J Clin Invest. 1983;71(6):1887–92.CrossRefPubMedPubMedCentral
34.
Hirschhorn R, Ellenbogen A. Genetic heterogeneity in adenosine deaminase (ADA) deficiency: five different mutations in five new patients with partial ADA deficiency. Am J Hum Genet. 1986;38(1):13–25.PubMedPubMedCentral
35.
Arredondo-Vega FX, Santisteban I, Kelly S, Schlossman CM, Umetsu DT, Hershfield MS. Correct splicing despite mutation of the invariant first nucleotide of a 5′ splice site: a possible basis for disparate clinical phenotypes in siblings with adenosine deaminase deficiency. Am J Hum Genet. 1994;54(5):820–30.PubMedPubMedCentral
36.
Jenkins T, Rabson AR, Nurse GT, Lane AB. Deficiency of adenosine deaminase not associated with severe combined immunodeficiency. J Pediatr. 1976;89(5):732–6.CrossRefPubMed
37.
Hart SL, Lane AB, Jenkins T. Partial adenosine deaminase deficiency: another family from southern Africa. Hum Genet. 1986;74(3):307–12.CrossRefPubMed
38.
Chan B, Wara D, Bastian J, et al. Long-term efficacy of enzyme replacement therapy for adenosine deaminase (ADA)-deficient severe combined immunodeficiency (SCID). Clin Immunol. 2005;117(2):133–43.CrossRefPubMed
39.
Kohn DB, Gaspar HB. How we manage adenosine deaminase-deficient severe combined immune deficiency (ADA SCID). J Clin Immunol. 2017;37(4):351–6.CrossRefPubMed
40.
Hassan A, Booth C, Brightwell A, et al. Outcome of hematopoietic stem cell transplantation for adenosine deaminase-deficient severe combined immunodeficiency. Blood. 2012;120(17):3615–24. quiz 3626CrossRefPubMed
41.
Blaese RM, Culver KW, Miller AD, et al. T lymphocyte-directed gene therapy for ADA- SCID: initial trial results after 4 years. Science. 1995;270(5235):475–80.CrossRefPubMed
42.
Bordignon C, Notarangelo LD, Nobili N, et al. Gene therapy in peripheral blood lymphocytes and bone marrow for ADA- immunodeficient patients. Science. 1995;270(5235):470–5.CrossRefPubMed
43.
Ferrari G, Rossini S, Giavazzi R, et al. An in vivo model of somatic cell gene therapy for human severe combined immunodeficiency. Science. 1991;251(4999):1363–6.CrossRefPubMed
44.
Cicalese MP, Ferrua F, Castagnaro L, et al. Update on the safety and efficacy of retroviral gene therapy for immunodeficiency due to adenosine deaminase deficiency. Blood. 2016;128(1):45–54.CrossRefPubMedPubMedCentral
45.
Aiuti A, Roncarolo MG, Naldini L. Gene therapy for ADA-SCID, the first marketing approval of an ex vivo gene therapy in Europe: paving the road for the next generation of advanced therapy medicinal products. EMBO Mol Med. 2017;9(6):737–40.CrossRefPubMedPubMedCentral
46.
Aiuti A, Slavin S, Aker M, et al. Correction of ADA-SCID by stem cell gene therapy combined with nonmyeloablative conditioning. Science. 2002;296(5577):2410–3.CrossRefPubMed
47.
Aiuti A, Cattaneo F, Galimberti S, et al. Gene therapy for immunodeficiency due to adenosine deaminase deficiency. N Engl J Med. 2009;360(5):447–58.CrossRefPubMed
48.
Shaw KL, Garabedian E, Mishra S, et al. Clinical efficacy of gene-modified stem cells in adenosine deaminase-deficient immunodeficiency. J Clin Invest. 2017;127(5):1689–99.CrossRefPubMedPubMedCentral
49.
Ott MG, Schmidt M, Schwarzwaelder K, et al. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med. 2006;12(4):401–9.CrossRefPubMed
50.
Braun CJ, Boztug K, Paruzynski A, et al. Gene therapy for Wiskott-Aldrich syndrome--long-term efficacy and genotoxicity. Sci Transl Med. 2014;6(227):227ra233.CrossRef
51.
Hacein-Bey-Abina S, Garrigue A, Wang GP, et al. Insertional oncogenesis in 4 patients after retrovirus-mediated gene therapy of SCID-X1. J Clin Invest. 2008;118(9):3132–42.CrossRefPubMedPubMedCentral
52.
Carbonaro DA, Zhang L, Jin X, et al. Preclinical demonstration of lentiviral vector-mediated correction of immunological and metabolic abnormalities in models of adenosine deaminase deficiency. Mol Ther. 2014;22(3):607–22.CrossRefPubMedPubMedCentral
53.
Gaspar HB, Buckland K, Carbonaro DA, et al. C-8. Immunological and metabolic correction after lentiviral vector gene therapy for ADA deficiency. Mol Ther. 2015;23(Supplement 1):S102–3.CrossRef
54.
55.
Adams SP, Rashid S, Premachandra T, et al. Screening of neonatal UK dried blood spots using a duplex TREC screening assay. J Clin Immunol. 2014;34(3):323–30.CrossRefPubMed
56.
Brown L, Xu-Bayford J, Allwood Z, et al. Neonatal diagnosis of severe combined immunodeficiency leads to significantly improved survival outcome: the case for newborn screening. Blood. 2011;117(11):3243–6.CrossRefPubMed
Metadata
Title
Adenosine deaminase deficiency: a review
Authors
Aisling M. Flinn
Andrew R. Gennery
Publication date
01-12-2018
Publisher
BioMed Central
Published in
Orphanet Journal of Rare Diseases / Issue 1/2018
Electronic ISSN: 1750-1172
DOI
https://doi.org/10.1186/s13023-018-0807-5

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