NCBI Bookshelf. Adenosine deaminase ADA deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. The clinical phenotypic spectrum includes:. 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.

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NCBI Bookshelf. Adenosine deaminase ADA deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function. The clinical phenotypic spectrum includes:. 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.

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. The diagnosis of ADA deficiency is established in a proband :.

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. For these individuals, alternative therapies can be considered:.

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. ADA deficiency is inherited in an autosomal recessive manner.

Carrier testing for at-risk family members and prenatal testing for pregnancies at increased risk are possible once the pathogenic variants have been identified in the family. View in own window. For other genetic causes of these phenotypes see Differential Diagnosis. Adenosine deaminase ADA deficiency should be suspected in individuals with the following newborn screening results, clinical findings by age , and supportive laboratory findings.

Note: 1 In recently transfused individuals, a deficiency of ADA catalytic activity can be demonstrated in extracts of non-erythroid cells e. Additionally, plasma contains adenosine deaminase activity as a result of another enzyme known as ADA2 see Differential Diagnosis. Molecular genetic testing approaches can include single- gene testing and use of a multigene panel :. See Table A. Genes and Databases for chromosome locus and protein. See Molecular Genetics for information on allelic variants detected in this gene.

Sequence analysis detects variants that are benign, likely benign, of uncertain significance , likely pathogenic, or pathogenic. For issues to consider in interpretation of sequence analysis results, click here. Methods that may be used include quantitative PCR , long-range PCR, multiplex ligation-dependent probe amplification MLPA , and a gene -targeted microarray designed to detect single- exon deletions or duplications.

Affected individuals present in the first weeks to months of life with failure to thrive and opportunistic infections associated with marked lymphocytopenia and the absence of both humoral and cellular immune function. The diagnosis of SCID is often made within the first six months of life and usually by age 12 months.

Persistent diarrhea, extensive dermatitis, recurrent pneumonia, and other life-threatening illnesses caused by opportunistic infections occur frequently. The initial hospitalization is often for pneumonitis, which may result from viral or Pneumocystis jiroveci infection.

However, a causative agent often cannot be identified. Noninfectious lung disease appears to occur more frequently in individuals with ADA deficiency than with other genetic forms of SCID [ Booth et al ]. Pulmonary dysfunction in those with ADA deficiency has also been identified using the effort-independent technique of impulse oscillometry [ Komarow et al ]. Physical findings include growth failure, the absence of lymphoid tissues tonsils, lymph nodes , and the effects of specific infections.

Thymus shadow is absent on x-ray. Characteristic anterior rib cupping, scapular spurring, and other skeletal abnormalities are present at diagnosis in about half of individuals with ADA deficiency. These abnormalities appear to resolve after a few months of treatment [ Manson et al ]. Other organ involvement. In addition to marked depletion of T, B, and NK lymphocytes, some individuals with ADA deficiency may show reduced neutrophil counts and bone marrow abnormalities including myeloid dysplasia and hypocellularity [ Sokolic et al ].

It is often unclear whether these hepatic and neurologic abnormalities are caused by the metabolic effects of ADA deficiency itself or are secondary to the immunodeficiency i. However, in some individuals, hepatic and neurologic abnormalities have improved or resolved with institution of enzyme replacement therapy.

Infections in delayed- and late-onset types may initially be less severe than in those individuals with full-blown SCID, and growth may be less severely affected. Recurrent otitis, sinusitis, and upper respiratory infections are common. Palmar and plantar warts may be persistent, and older individuals have presented with unusual papilloma viral infections [ Antony et al , Artac et al ]. By the time of diagnosis, these individuals often have chronic pulmonary insufficiency and possibly autoimmune phenomena, including cytopenias and anti-thyroid antibodies [ Sauer et al ].

Allergies and elevated serum concentration of IgE are common. Individuals with a delayed- or late-onset phenotype may survive undiagnosed into the first decade of life or beyond.

However, the longer the disorder goes unrecognized, the more immune function deteriorates and the more likely are chronic sequelae of recurrent respiratory and other types of infection. This benign condition, which is compatible with normal immune function, has been called "partial ADA deficiency.

Most known ADA pathogenic variants have been discovered through research into the relationship of genotype to phenotype [ Hirschhorn et al , Santisteban et al , Arredondo-Vega et al , Ozsahin et al ]. Systematic expression in E coli of more than 30 cDNAs with single missense variants identified in ADA-deficient individuals has shown that the total ADA activity expressed by both of an individual's mutated alleles correlates with age at diagnosis and the level of erythrocyte dAXP measured prior to treatment [ Arredondo-Vega et al ].

A system for ranking the severity of genotypes has been proposed based on these data and the potential of other alleles to provide ADA activity.

For this purpose, individual pathogenic ADA alleles are clustered in groups, as follows:. Phenotype correlation with pathogenic variant type was assessed for 52 clinically diverse individuals with 43 genotypes composed of 42 different pathogenic alleles [ Arredondo-Vega et al ]:. Discordance in phenotype among first-degree ADA-deficient relatives in several families has been attributed to the following:.

ADA deficiency has been estimated to occur in from , to ,, births. As information from newborn screening becomes available, estimates of the incidence of ADA deficiency may change. All racial and ethnic groups are affected.

Prevalence is higher in some geographic areas where a high degree of consanguinity exists in certain population groups. No phenotypes other than those described in this GeneReview are associated with pathogenic variants in ADA. Purine nucleoside phosphorylase PNP deficiency OMIM is an inborn error of purine metabolism that causes autosomal recessive immunodeficiency, which in some respects is similar clinically and pathophysiologically to adenosine deaminase ADA deficiency [ Hershfield ].

Biochemical testing for both ADA and PNP deficiency should be performed in individuals with immunodeficiency who are suspected of having either disorder.

The SCID phenotype can also result from pathogenic variants in other genes [ Buckley , Fischer et al , Dvorak et al , Shearer et al ]. These disorders are similar clinically, but some have characteristic patterns of lymphocyte depletion that can be determined by flow cytometric enumeration of T, B, and natural killer NK cells in peripheral blood. The initial individuals identified with DADA2 deficiency had clinical features of an autoinflammatory condition associated with vasculopathy, but many also had immunodeficiency, usually manifested by reduced serum IgM and abnormalities of the B lymphocyte lineage.

See Adenosine Deaminase 2 Deficiency. HIV-AIDS should be considered in individuals with T lymphopenia and opportunistic infections, but the retroviral infection can be identified by specific testing. For older individuals with delayed- and late-onset phenotypes, cystic fibrosis , common variable immunodeficiency OMIM PS , and PNP deficiency could also be considered. Measurement of cellular ADA activity definitively distinguishes ADA deficiency from all other disorders associated with compatible clinical features.

To establish the extent of disease and needs in an individual diagnosed with adenosine deaminase ADA deficiency, the following evaluations are recommended, some of which may be performed as part of the diagnostic evaluation:. Restoring a functional immune system is essential and can be achieved in several ways. A workshop held in developed consensus guidelines for therapy [ Gaspar et al ] full text. Following a T-cell-depleted transplant, return of functional T-cells requires three to four months.

B-cell reconstitution is delayed longer, or may not be adequately achieved, requiring long-term immunoglobulin replacement therapy. When considering therapeutic options, it is therefore important for parents to obtain specific information about prior experience and long-term results of transplants for ADA-deficient SCID at the center where their child will be treated.

Lymphocyte counts and in vitro lymphocyte function usually increase during the first year of ERT, but beyond the first year or two most PEG-ADA-treated individuals remain lymphopenic and in vitro lymphocyte function fluctuates widely. Most individuals remain clinically well, but over time both T and B lymphocytes gradually decline in number and display various functional abnormalities [ Chan et al , Malacarne et al , Serana et al , Brigida et al ].

Approximately half of those maintained on ERT were continuing to receive immunoglobulin replacement. Most deaths occurred during the first six months of treatment, with the majority in the first month due to life-threatening infections present at diagnosis. Lymphoproliferative disorders have developed in eight individuals who received PEG-ADA for eight to 22 years [ Hershfield ; Chan et al ; Kaufman et al ; Husain et al ; Author, unpublished data].

Hepatocellular carcinoma developed in one affected individual after 13 years of ERT, and was present in another at the time ERT was initiated following an unsuccessful stem cell transplant. A third affected individual died of hepatoblastoma after 2. Several other affected individuals have developed persistent hemolytic anemia, which in some cases began in association with a viral infection or with central catheter sepsis [ Hershfield , Lainka et al ].

The limitations of PEG-ADA therapy include primary failure to recover protective immune function, the development of neutralizing antibodies that reduce or eliminate efficacy, immune dysregulation particularly in the first few months of therapy , and a risk that immune function will eventually i. In most of these cases, the transplant had been intended at the time of diagnosis but not performed because a suitable donor was not available or the affected individual had been too ill to undergo the procedure.

In a minority of individuals, the transplant was performed because of declining immune function while receiving PEG-ADA. Overall, approximately half of these secondary transplants have been successful [ Hershfield , Gaspar et al ]. No allergic or hypersensitivity reactions to PEG-ADA have occurred, and the treatment has generally been well tolerated.

Gene therapy , while still technically experimental, is still another treatment option for those who have failed all other options see Therapies Under Investigation. As noted under Treatment of Manifestations , affected individuals receive antibiotic prophylaxis for Pneumocystis , and also IVIG, prior to immune reconstitution. The use of such prophylaxis following transplantation and while receiving ERT varies and depends on the level of immune reconstitution achieved.

Annual or more frequent evaluation of lymphocyte counts, serum immunoglobulin levels, and various in vitro tests of cellular and humoral immune function i. The use of adenine arabinoside a substrate for ADA as an antiviral agent or for chemotherapy of malignancies should be avoided. It is appropriate to evaluate newborn sibs of a proband so that morbidity and mortality can be reduced by early diagnosis and treatment.

Evaluations can include:. See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Experimental gene therapy for ADA-deficient SCID employing gamma retroviral vectors has been under clinical investigation for more than 20 years [ Engel et al , Cavazzana-Calvo et al ]. Clinical trials since about have employed an approach that was first reported for two affected individuals treated in Milan, Italy and later updated for ten others [ Aiuti et al , Aiuti et al ].

In most treated individuals, stable ADA expression in lymphoid cells has been achieved, along with correction of metabolic abnormalities in erythrocytes, which has been accompanied by reconstitution of both T and B cell immune function, although this reconstitution may take a year or more. Good health has been maintained without the need for ERT.


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Only comments seeking to improve the quality and accuracy of information on the Orphanet website are accepted. For all other comments, please send your remarks via contact us. Only comments written in English can be processed. Severe combined immunodeficiency SCID due to adenosine deaminase ADA deficiency is a form of SCID characterized by profound lymphopenia and very low immunoglobulin levels of all isotypes resulting in severe and recurrent opportunistic infections.


Adenosine deaminase deficiency

Adenosine deaminase deficiency is an autosomal recessive [1] metabolic disorder that causes immunodeficiency. It occurs in fewer than one in , live births worldwide. Age of onset and severity is related to some 29 known genotypes associated with the disorder. The main symptoms of ADA deficiency are pneumonia, chronic diarrhea, and widespread skin rashes.

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