Clinical characteristics: Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. The clinical phenotypic spectrum includes:
Severe combined immunodeficiency disease (SCID), often diagnosed by age six months and usually by age 12 months;
Less severe "delayed" onset combined immune deficiency (CID), usually diagnosed between age one and ten years;
"Late/adult onset" CID, diagnosed in the second to fourth decades;
Benign "partial ADA deficiency" (very low or absent ADA activity in erythrocytes but greater ADA activity in nucleated cells), which is compatible with normal immune function.
Infants with typical early-onset ADA-deficient SCID have failure to thrive and opportunistic infections associated with marked depletion of T, B, and NK lymphocytes, and an absence of both humoral and cellular immune function. If immune function is not restored, children with ADA-deficient SCID rarely survive beyond age one to two years. Infections in delayed- and late-onset types (commonly, recurrent otitis, sinusitis, and upper respiratory) may initially be less severe than those in individuals with ADA-deficient SCID; however, by the time of diagnosis these individuals often have chronic pulmonary insufficiency and may have autoimmune phenomena (cytopenias, anti-thyroid antibodies), allergies, and elevated serum concentration of IgE. The longer the disorder goes unrecognized, the more immune function deteriorates and the more likely are chronic sequelae of recurrent infection.
Diagnosis/testing: The diagnosis of ADA deficiency is established in a proband:
With <1% of normal ADA catalytic activity in hemolysates (in untransfused individuals) or in extracts of other cells (e.g., blood mononuclear cells, fibroblasts); AND/OR
By the identification of biallelic pathogenic variants in ADA by molecular genetic testing.
Management: Treatment of manifestations: Infections are treated with specific antibiotic, antifungal, and antiviral agents and administration of intravenous immunoglobulin (IVIg); prophylaxis is provided for Pneumocystis jiroveci infection.
Prevention of primary manifestations: Restoration of a functional immune system is essential. The preferred treatment is bone marrow/stem cell transplantation (BMT/SCT) from an HLA-identical healthy sib or close relative. However, most individuals with ADA-deficient SCID lack an HLA-identical related donor. For these individuals, alternative therapies can be considered:
BMT/SCT from a "non-ideal" donor, which may be an HLA-matched unrelated donor, an HLA-haploidentical donor (usually a parent), or umbilical cord-derived stem cells
Enzyme replacement therapy (ERT) with polyethylene glycol-modified bovine adenosine deaminase (PEG-ADA)
Gene therapy, which is currently experimental
Surveillance: Annual or more frequent evaluation of lymphocyte counts, serum immunoglobulin levels, and various in vitro tests of cellular and humoral immune function following BMT/SCT and during ERT (more frequent monitoring and other specialized testing would be required for participants in gene therapy trials). Individuals on ERT also require periodic monitoring of PEG-ADA levels in plasma and metabolite levels in erythrocytes, and under some circumstances testing for anti-ADA antibodies.
Agents/circumstances to avoid: The use of adenine arabinoside (a substrate for ADA) as an antiviral agent or for chemotherapy of malignancies should be avoided; pentostatin, a potent ADA inhibitor used to treat some lymphoid malignancies, would be ineffective in persons who lack ADA, and would interfere with PEG-ADA.
Evaluation of relatives at risk: In the newborn sibs of a proband, it is appropriate to either assay ADA catalytic activity or perform molecular genetic testing (if the family-specific pathogenic variants are known), so that morbidity and mortality can be reduced by early diagnosis and treatment.
Genetic counseling: ADA deficiency is inherited in an autosomal recessive manner. At conception, each sib of an affected individual has a 25% chance of being affected, a 50% chance of being an asymptomatic carrier, and a 25% chance of being unaffected and not a carrier. Carrier testing for at-risk family members and prenatal testing for a pregnancy at increased risk are possible once the pathogenic variants have been identified in the family.
Copyright © 1993-2024, University of Washington, Seattle. GeneReviews is a registered trademark of the University of Washington, Seattle. All rights reserved.