Adenosine deaminase deficiency

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Adenosine deaminase deficiency
ICD-10 D81.3
ICD-9 279.2
OMIM 102700
DiseasesDB 260

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Shyam Patel [2];Associate Editor(s)-in-Chief: Mohsen Basiri M.D.

Synonyms and Keywords: ADA Deficiency; SCID Due to ADA Deficiency; ADA-SCID

Overview

Adenosine deaminase deficiency, or ADA deficiency, is an inherited immunodeficiency syndrome accounting for about 15% of all cases of severe combined immunodeficiency (SCID). This disease is due to a lack of the enzyme adenosine deaminase coded for by a gene on chromosome 20. There is an accumulation of dATP, which causes an increase in S-adenosylhomocysteine; both substances are toxic to immature lymphoid cells, so fail to reach maturity. As a result, the immune system of the afflicted person is severely compromised or completely lacking. The enzyme adenosine deaminase is important for purine metabolism.

Historical Perspective

  • Adenosine deaminase (ADA) deficiency was first discovered by Dr. Eloise Giblett in 1972, when she received samples from a patient with severe combined immunodeficiency (SCID) that was a candidate for bone marrow transplantation; examination of blood samples presented that the patients have no ADA activity.
  • With discovering the second case with ADA deficiency and immunodeficiency, ADA deficiency was the first immunodeficiency in which the specific molecular defect was described.[1]

Classification

  • There is no established system for the classification of adenosine deaminase deficiency.

Pathophysiology

Causes

  • Adenosine deaminase deficiency is a disorder arising from a mutation in the ADA1 gene at 20q13.11.

Differentiating Adenosine deaminase deficiency from Other Diseases

  • Adenosine deaminase deficiency must be differentiated from other diseases that cause clinical features of severe combined immunodeficiency , and complete DiGeorge syndrome. Although DiGeorge syndrome is associated with facial and cardiac anomalies which are not seen with ADA deficiency.[5]

Epidemiology and Demographics

Risk Factors

  • There are no established risk factors for adenosine deaminase deficiency.

Screening

  • ADA deficiency can be diagnosed in a newborn before the beginning of infections, with one well-documented example by screening of T-cell–receptor excision circles(TRECs).TRECs, formed during the differentiation of T cells in the thymus.
  • A quantitative real-time polymerase chain reaction(PCR) test can measure T cell receptor excision circles. TRECs serve as a biomarker of naïve T cells, which is a sensitive and specific, as well as cost effective method for ADA deficiency newborn screening.[8]

Natural History, Complications, and Prognosis

Natural History

Complications

  • Patients are at risk for opportunistic infections usually follow more common infections. P. jiroveci and fungal pneumonias cause death in classic cases.
  • CMV, VZV, and HSV infections typically occur in infants who have already had treatable infections. Neurologic compromise from polio and other enteroviruses impede stem cell reconstitution.[12]
  • Lymphoma is an invariably fatal complication that occurs among patients with a later onset and in patients treated successfully with enzyme replacement therapy.[13]

Prognosis

  • ADA deficiency is fatal, generally within the first year of life, unless the underlying defect is corrected.
  • Early diagnosis through population-wide newborn screening and early transplantation in the absence of infectious complications may improve hematopoietic cell transplantation (HCT) outcomes.
  • Among patients transplanted under 3.5 months of age without infection, survival post-transplant is about 95 percent, and overall survival is 90 percent.[14]

Diagnosis

Diagnostic Criteria

  • The diagnosis of adenosine deaminase deficiency is made by following finding:[15]

History and Symptoms

Physical Examination

Physical findings are multisystemic. The patient may present with the following:[17]

Laboratory Findings

Laboratory findings consistent with the diagnosis of ADA deficiency include :[18]

Imaging Findings

  • A chest x-ray may be helpful in the diagnosis of adenosine deaminase deficiency. The thymic shadow is absent on chest radiography among the majority of patients with adenosine deaminase deficiency, thus, a chest x-ray may be helpful in the newborn suspected of adenosine deaminase deficiency.
  • Chest x-ray reveals the flaring of the anterior ribs, pelvic dysplasia, and shortening of the transverse vertebral processes with flattening of their ends and thick growth arrest lines. In addition, obtaining a chest x-ray may be helpful to assess pneumonia secondary to adenosine deaminase deficiency.[19]

Treatment

Medical Therapy

  • The mainstay of treatment for adenosine deaminase (ADA) deficiency with severe combined immunodeficiency phenotype is hematopoietic cell transplantation(HCT) from a human leukocyte antigen (HLA)-identical sibling, or if not available, a matched family donor.
  • If a matched sibling or family donor is not an option, then gene therapy is suggested, if available and not cost prohibitive, for an infant or young child with ADA-deficient SCID.
  • The majority of cases of adenosine deaminase deficiency require enzyme replacement therapy with polyethylene glycol-adenosine deaminase [PEG-ADA].[20]

Primary Prevention

  • There are no established measures for the primary prevention of adenosine deaminase deficiency.

Secondary Prevention

Effective measures for the secondary prevention of adenosine deaminase deficiency include:[21]

Typical prophylaxis against infection includes:

References

  1. Motulsky A, Gartler S. "Biographical Memoirs: Eloise R. Giblett". National Academy of Sciences
  2. D. A. Wiginton, G. S. Adrian, R. L. Friedman, D. P. Suttle & J. J. Hutton (1983). "Cloning of cDNA sequences of human adenosine deaminase". Proceedings of the National Academy of Sciences of the United States of America. 80 (24): 7481–7485. PMID 6200875. Unknown parameter |month= ignored (help)
  3. M. S. Hershfield, N. M. Kredich, D. R. Ownby, H. Ownby & R. Buckley (1979). "In vivo inactivation of erythrocyte S-adenosylhomocysteine hydrolase by 2'-deoxyadenosine in adenosine deaminase-deficient patients". The Journal of clinical investigation. 63 (4): 807–811. doi:10.1172/JCI109367. PMID 312296. Unknown parameter |month= ignored (help)
  4. R. H. Buckley, R. I. Schiff, S. E. Schiff, M. L. Markert, L. W. Williams, T. O. Harville, J. L. Roberts & J. M. Puck (1997). "Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants". The Journal of pediatrics. 130 (3): 378–387. PMID 9063412. Unknown parameter |month= ignored (help)
  5. Fausto Cossu (2010). "Genetics of SCID". Italian journal of pediatrics. 36: 76. doi:10.1186/1824-7288-36-76. PMID 21078154. Unknown parameter |month= ignored (help)
  6. R. H. Buckley, R. I. Schiff, S. E. Schiff, M. L. Markert, L. W. Williams, T. O. Harville, J. L. Roberts & J. M. Puck (1997). "Human severe combined immunodeficiency: genetic, phenotypic, and functional diversity in one hundred eight infants". The Journal of pediatrics. 130 (3): 378–387. PMID 9063412. Unknown parameter |month= ignored (help)
  7. Kee Chan & Jennifer M. Puck (2005). "Development of population-based newborn screening for severe combined immunodeficiency". The Journal of allergy and clinical immunology. 115 (2): 391–398. doi:10.1016/j.jaci.2004.10.012. PMID 15696101. Unknown parameter |month= ignored (help)
  8. John M. Routes, William J. Grossman, James Verbsky, Ronald H. Laessig, Gary L. Hoffman, Charles D. Brokopp & Mei W. Baker (2009). "Statewide newborn screening for severe T-cell lymphopenia". JAMA. 302 (22): 2465–2470. doi:10.1001/jama.2009.1806. PMID 19996402. Unknown parameter |month= ignored (help)
  9. Jennifer M. Puck (2011). "Neonatal screening for severe combined immunodeficiency". Current opinion in pediatrics. 23 (6): 667–673. doi:10.1097/MOP.0b013e32834cb9b0. PMID 22001765. Unknown parameter |month= ignored (help)
  10. Kathryn V. Whitmore & Hubert B. Gaspar (2016). "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency". Frontiers in immunology. 7: 314. doi:10.3389/fimmu.2016.00314. PMID 27579027.
  11. A. Fischer (2000). "Severe combined immunodeficiencies (SCID)". Clinical and experimental immunology. 122 (2): 143–149. PMID 11091267. Unknown parameter |month= ignored (help)
  12. G. Morgan, R. J. Levinsky, K. Hugh-Jones, L. D. Fairbanks, G. S. Morris & H. A. Simmonds (1987). "Heterogeneity of biochemical, clinical and immunological parameters in severe combined immunodeficiency due to adenosine deaminase deficiency". Clinical and experimental immunology. 70 (3): 491–499. PMID 3436096. Unknown parameter |month= ignored (help)
  13. Maitham Husain, Eyal Grunebaum, Ahmed Naqvi, Adelle Atkinson, Bo-Yee Ngan, Alessandro Aiuti & Chaim M. Roifman (2007). "Burkitt's lymphoma in a patient with adenosine deaminase deficiency-severe combined immunodeficiency treated with polyethylene glycol-adenosine deaminase". The Journal of pediatrics. 151 (1): 93–95. doi:10.1016/j.jpeds.2007.03.059. PMID 17586199. Unknown parameter |month= ignored (help)
  14. Jennifer Heimall, Brent R. Logan, Morton J. Cowan, Luigi D. Notarangelo, Linda M. Griffith, Jennifer M. Puck, Donald B. Kohn, Michael A. Pulsipher, Suhag Parikh, Caridad Martinez, Neena Kapoor, Richard O'Reilly, Michael Boyer, Sung-Yun Pai, Frederick Goldman, Lauri Burroughs, Sharat Chandra, Morris Kletzel, Monica Thakar, James Connelly, Geoff Cuvelier, Blachy J. Davila Saldana, Evan Shereck, Alan Knutsen, Kathleen E. Sullivan, Kenneth DeSantes, Alfred Gillio, Elie Haddad, Aleksandra Petrovic, Troy Quigg, Angela R. Smith, Elizabeth Stenger, Ziyan Yin, William T. Shearer, Thomas Fleisher, Rebecca H. Buckley & Christopher C. Dvorak (2017). "Immune reconstitution and survival of 100 SCID patients post-hematopoietic cell transplant: a PIDTC natural history study". Blood. 130 (25): 2718–2727. doi:10.1182/blood-2017-05-781849. PMID 29021228. Unknown parameter |month= ignored (help)
  15. Capucine Picard, Waleed Al-Herz, Aziz Bousfiha, Jean-Laurent Casanova, Talal Chatila, Mary Ellen Conley, Charlotte Cunningham-Rundles, Amos Etzioni, Steven M. Holland, Christoph Klein, Shigeaki Nonoyama, Hans D. Ochs, Eric Oksenhendler, Jennifer M. Puck, Kathleen E. Sullivan, Mimi L. K. Tang, Jose Luis Franco & H. Bobby Gaspar (2015). "Primary Immunodeficiency Diseases: an Update on the Classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency 2015". Journal of clinical immunology. 35 (8): 696–726. doi:10.1007/s10875-015-0201-1. PMID 26482257. Unknown parameter |month= ignored (help)
  16. M. E. Bollinger, F. X. Arredondo-Vega, I. Santisteban, K. Schwarz, M. S. Hershfield & H. M. Lederman (1996). "Brief report: hepatic dysfunction as a complication of adenosine deaminase deficiency". The New England journal of medicine. 334 (21): 1367–1371. doi:10.1056/NEJM199605233342104. PMID 8614422. Unknown parameter |month= ignored (help)
  17. Magda Carneiro-Sampaio, Cristina Miuki Abe Jacob & Clea Rodrigues Leone (2011). "A proposal of warning signs for primary immunodeficiencies in the first year of life". Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology. 22 (3): 345–346. doi:10.1111/j.1399-3038.2010.01084.x. PMID 21457340. Unknown parameter |month= ignored (help)
  18. J. Donofrio, M. S. Coleman, J. J. Hutton, A. Daoud, B. Lampkin & J. Dyminski (1978). "Overproduction of adenine deoxynucleosides and deoxynucletides in adenosine deaminase deficiency with severe combined immunodeficiency disease". The Journal of clinical investigation. 62 (4): 884–887. doi:10.1172/JCI109201. PMID 308954. Unknown parameter |month= ignored (help)
  19. Kathryn V. Whitmore & Hubert B. Gaspar (2016). "Adenosine Deaminase Deficiency - More Than Just an Immunodeficiency". Frontiers in immunology. 7: 314. doi:10.3389/fimmu.2016.00314. PMID 27579027.
  20. H. Bobby Gaspar (2010). "Bone marrow transplantation and alternatives for adenosine deaminase deficiency". Immunology and allergy clinics of North America. 30 (2): 221–236. doi:10.1016/j.iac.2010.01.002. PMID 20493398. Unknown parameter |month= ignored (help)
  21. Linda M. Griffith, Morton J. Cowan, Luigi D. Notarangelo, Jennifer M. Puck, Rebecca H. Buckley, Fabio Candotti, Mary Ellen Conley, Thomas A. Fleisher, H. Bobby Gaspar, Donald B. Kohn, Hans D. Ochs, Richard J. O'Reilly, J. Douglas Rizzo, Chaim M. Roifman, Trudy N. Small & William T. Shearer (2009). "Improving cellular therapy for primary immune deficiency diseases: recognition, diagnosis, and management". The Journal of allergy and clinical immunology. 124 (6): 1152–1160. doi:10.1016/j.jaci.2009.10.022. PMID 20004776. Unknown parameter |month= ignored (help)



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