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Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

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Adenosine Deaminase Deficiency

Synonyms: ADA Deficiency, ADA-SCID
, MD
Professor of Medicine and Biochemistry
Duke University Medical Center
Durham, North Carolina

Initial Posting: ; Last Update: June 19, 2014.

Summary

Disease 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. Diagnostic criteria for ADA deficiency:

  • Evidence of combined immunodeficiency (usually with very low T, B, and NK lymphocyte counts in peripheral blood) and an absence of thymus and other lymphoid tissues; and
  • Less than 1% of normal ADA catalytic activity in hemolysates (in un-transfused patients) or in extracts of other cells (e.g., blood mononuclear cells, fibroblasts)

ADA is the only gene associated with ADA deficiency. Sequence analysis can identify most known ADA pathogenic variants, except for large deletions, which are detected by deletion/duplication analysis.

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, Adagen®)
  • Gene therapy, which is currently experimental (enrollment is limited to ongoing clinical trials at about a half-dozen centers, worldwide)

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 pregnancies at increased risk are possible once the pathogenic variants have been identified in the family.

GeneReview Scope

Adenosine Deaminase Deficiency: Included Disorders
  • Adenosine deaminase-deficient severe combined immunodeficiency disease (SCID)
  • Delayed-/late-onset adenosine deaminase deficiency
  • Partial adenosine deaminase deficiency

Diagnosis

Clinical Diagnosis

Diagnostic criteria for adenosine deaminase (ADA) deficiency:

  • Evidence of combined immunodeficiency, usually with very low T, B, and NK lymphocyte counts in peripheral blood, and an absence of thymus and other lymphoid tissues
  • Less than 1% of normal ADA catalytic activity in hemolysates or extracts of dried blood spots (DBS), or in recently transfused individuals, in extracts of other cells (e.g., blood mononuclear cells, fibroblasts)

PreliminaryTests

Newborn screening. The profound reduction in T lymphocytes in nearly all forms of SCID can be identified in DBS from neonates by demonstrating a reduced level of T-cell receptor excision circles (TRECs) in extracted DNA. TREC screening is now performed in several states in the US and may be adopted by others. As about 15% of all cases of SCID result from ADA deficiency, biochemical testing for ADA deficiency should be performed as a follow up in all newborns who are positive by TREC screening.

Note: (1) Individuals with delayed or late/adult ADA deficiency may have TRECs in the normal range. (2) Reduced levels of a B lymphocyte marker, kappa-deleting recombination excision circles (KRECs), have also been found in DNA from DBS of individuals with delayed- or late-onset ADA deficiency [Speckmann et al 2012].

Immune function

  • Lymphopenia, the laboratory hallmark of ADA-deficient severe combined immunodeficiency disease (SCID), is present at birth. The total blood lymphocyte count is usually lower than 500/µL (normal for neonates: 2,000 to >5,000).
  • All lymphoid lineages (T-, B-, and NK-cells) are depleted as demonstrated by flow cytometry.
  • In vitro lymphocyte function, as measured by proliferative response to mitogens and antigens, is low or absent.
  • Serum immunoglobulins are low and no specific antibody response to infections and immunizations is observed.

Biochemical markers of ADA deficiency. The severe deficiency of ADA results in specific metabolic abnormalities in blood and urine [Hershfield & Mitchell 2001]. These markers may help to confirm the diagnosis and to monitor therapies intended to restore ADA function.

  • Elevated deoxyadenosine triphosphate (dATP) or total dAdo nucleotides (dAXP) in erythrocytes. Mature red cells normally lack dAXP. In the absence of ADA, excessive dAdo phosphorylation leads to a marked increase in dATP and total dAXP, a finding pathognomonic for ADA deficiency (it does not occur with ADA2 deficiency). In untreated affected individuals, the level of dAXP in hemolysates or DBS extracts correlates with clinical phenotype (SCID > "delayed/late" onset > "partial ADA deficiency"). Even after transfusion, some elevation in erythrocyte dAXP persists and strongly indicates underlying ADA deficiency.
  • Reduced S-adenosylhomocysteine hydrolase (AdoHcyase, SAHase) activity in erythrocytes. Owing to inactivation by dAdo, erythrocyte AdoHcyase (sometimes abbreviated SAHase) activity is less than 5% of normal.
  • Elevated Urinary dAdo. Excretion of dAdo is markedly elevated in untreated affected individuals.
  • Elevated levels of Ado and dAdo in extracts of dried blood spots (DBS), quantified using tandem mass spectrometry, is a sensitive method for screening neonates for ADA deficiency [Azzari et al 2011, Speckmann et al 2012, la Marca et al 2013].

Establishing the Diagnosis

Adenosine deaminase (ADA) catalytic activity

  • Affected individuals who have not been transfused have less than 1% of normal ADA catalytic activity in erythrocyte hemolysates or in DBS extracts.
  • Affected individuals who have been recently transfused may require testing of another cell type, such as fibroblasts or leukocytes.

Note: (1) Several spectrophotometric and radiochemical methods, as well commercial kits, have been used to assay ADA catalytic activity in hemolysates and DBS extracts. The concentration of substrate, adenosine (Ado), or 2’-deoxyadenosine (dAdo), is generally 150-300 µM, reflecting the 25-50 µM Km of ADA1, encoded by ADA. (2) Analysis of ADA enzymatic activity in plasma is not useful for diagnosis because ADA activity is much lower in plasma than in cells, even in normal (non ADA-deficient) individuals, and because plasma contains adenosine deaminase activity caused by another enzyme known as ADA2. ADA2 has a much lower affinity for substrate (Km ~2 mM) and, unlike ADA1, is insensitive to inhibition by EHNA (erythro-9-(2-hydroxy-3-nonyl)adenine), which allows ADA1 and ADA2 to be quantitated independently. A deficiency of ADA2, caused by pathogenic variants in CECR1 and resulting in a systemic vasculopathy associated with symptoms of auto-inflammation, has recently been discovered [Zhou et al 2014].

Molecular Genetic Testing

Gene. ADA is the only gene in which pathogenic variants cause ADA deficiency.

Clinical testing

Table 1. Summary of Molecular Genetic Testing Used in Adenosine Deaminase Deficiency

Gene 1Test MethodProportion of Probands with a Pathogenic Variant Detectable by this Method
ADASequence analysis 2>90% 3
Deletion/duplication analysis 4Approximately 3% 5

1. See Table A. Genes and Databases for chromosome locus and protein name. See Molecular Genetics for information on allelic variants detected in this gene.

2. Sequence analysis detects variants that are benign, likely benign, of unknown significance, likely pathogenic, or pathogenic. Pathogenic variants may include small intragenic deletions/insertions and missense, nonsense, and splice site variants; typically, exonic or whole-gene deletions/duplications are not detected. For issues to consider in interpretation of sequence analysis results, click here.

3. In individuals with biochemically documented ADA deficiency

4. Testing that identifies exonic or whole-gene deletions/duplications not detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA. Included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.

5. Hirschhorn [1999], Hershfield & Mitchell [2001], Vihinen et al [2001]

Interpretation of test results. If novel single nucleotide changes are within the coding region, the effect on ADA enzymatic activity should be assessed (e.g., by expressing an ADA cDNA with the novel change in E coli).

Testing Strategy

To confirm/establish the diagnosis in a proband. Expeditious testing for ADA deficiency in individuals suspected of having SCID on clinical grounds, or who are well-appearing but have tested positive on newborn screening for SCID (see Preliminary Tests, Newborn screening), is critical because affected newborns already have, or are at high risk for acquiring, life-threatening infections, and because the therapeutic options for ADA deficiency are different from those for SCID caused by other molecular defects [Gaspar et al 2013].

  • Biochemical testing for the absence of ADA enzymatic activity in red cells is usually the most rapid means of diagnosis: results are often obtained within 24-48 hours. Finding of elevated dATP or dAXP in red cells or DBS confirms the diagnosis of ADA deficiency and is often informative in individuals with SCID who have been transfused.
  • Molecular genetic testing for ADA deficiency usually cannot be performed as rapidly as biochemical testing. However, once ADA deficiency has been diagnosed in a family and the pathogenic variants identified, molecular genetic testing can be used for carrier testing and prenatal testing.

Clinical Description

Natural History

Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development, viability, and function [Hirschhorn 1999, Hershfield & Mitchell 2001, Hershfield 2004]. The phenotypic spectrum associated with ADA deficiency includes early-onset SCID diagnosed in infancy; less severe "delayed/late" -onset combined immune deficiency (CID) diagnosed in older children and adults; and benign "partial ADA deficiency", which is discovered by screening populations or relatives of individuals with SCID for deficiency of erythrocyte ADA activity.

ADA-Deficient Severe Combined Immunodeficiency Disease (SCID)

The clinical picture in infants with typical early-onset ADA-deficient SCID is similar to that associated with SCID resulting from other genetic defects [Dvorak et al 2013, Shearer et al 2014]. 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. Non-infectious lung disease appears to occur more frequently in individuals with ADA deficiency than with other genetic forms of SCID [Booth et al 2012]. Pulmonary alveolar proteinosis has also been found more frequently in individuals with ADA-deficient SCID than in those with other forms of SCID [Grunebaum et al 2012].

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 2013].

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, such as myeloid dysplasia and hypocellularity [Sokolic et al 2011]. In some cases, abnormal liver function tests or various neurologic abnormalities (including sensorineural deafness) also occur and may be clinically significant [Bollinger et al 1996, Tanaka et al 1996, Rogers et al 2001, Albuquerque & Gaspar 2004, Nofech-Mozes et al 2007]. 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.e., to infections or to their treatment – e.g., with aminoglycoside antibiotics). However, in some individuals, hepatic and neurologic abnormalities have improved or resolved with institution of enzyme replacement therapy (ERT).

A rare malignant skin tumor, dermatofibrosarcoma protuberans (DFSP) has been identified in several individuals with ADA deficiency [Kesserwan et al 2012]. The natural history of DFSP in people with ADA deficiency is unknown at this time; surveillance is recommended.

If immune function is not restored, individuals with ADA-deficient SCID rarely survive beyond age one to two years.

Delayed-/Late-Onset ADA Deficiency

Approximately 15%-20% of children with ADA deficiency have a "delayed" onset of clinical symptoms, usually diagnosed between age one and ten years. Rarely, individuals are diagnosed in the second to fourth decades ("late/adult" onset). The immunologic abnormalities are less pronounced than in SCID and these affected individuals are usually referred to as having CID, or sometimes “leaky SCID” [Shearer et al 2014]. 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 2002, Artac et al 2010]. By the time of diagnosis, these individuals often have chronic pulmonary insufficiency and possibly autoimmune phenomena, including cytopenias and anti-thyroid antibodies. 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.

Partial ADA Deficiency

Screening of populations and families of probands with ADA-deficient SCID has identified some healthy individuals with very low or absent ADA activity in erythrocytes, but greater levels of ADA activity (2%-50% of normal) in nucleated cells. This benign condition, which is compatible with normal immune function, has been called “partial ADA deficiency.”

Genotype-Phenotype Correlations

Most known ADA pathogenic variants have been discovered through research into the relationship of genotype to phenotype [Hirschhorn et al 1990, Santisteban et al 1993, Arredondo-Vega et al 1994, Ozsahin et al 1997].

Systematic expression in E coli of more than 30 cDNAs with single missense mutations identified in ADA-deficient individuals has shown that the total ADA activity expressed by both of an individual's mutant alleles correlates with age at diagnosis and the level of erythrocyte dAXP measured prior to treatment [Arredondo-Vega et al 1998]. 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 mutant ADA alleles are clustered in groups, as follows:

  • Group 0. “Null” alleles (deletion, frameshifting, or nonsense mutations)
  • Groups I-IV. Missense mutations ranked in order of increasing activity expressed in the E coli system
  • Splice-site mutations. A separate group, as a low level of normal splicing may result in variable levels of ADA activity

Phenotype correlation with mutation type was assessed for 52 clinically diverse individuals with 43 genotypes composed of 42 different mutant alleles [Arredondo-Vega et al 1998]:

  • ADA-deficiency SCID. Both alleles scored as Group 0 or I.
  • Delayed-/late-onset ADA deficiency. At least one allele in Group II or III was detected.
  • Partial ADA deficiency. At least one Group IV allele was detected.

Discordance in phenotype among first-degree ADA-deficient relatives in several families has been attributed to the following:

Prevalence

ADA deficiency has been estimated to occur in from 1:200,000 to 1:1,000,000 births.

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.

Differential Diagnosis

Purine nucleoside phosphorylase (PNP) deficiency 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 2004]. Biochemical testing for both ADA and PNP deficiency should be performed in individuals with immunodeficiency who are suspected of having either disorder.

SCID can also result from pathogenic variants in other genes [Buckley 2004, Fischer et al 2005, Dvorak et al 2013, Shearer et al 2014]. 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 “T- B- NK-” pattern of lymphopenia in ADA deficiency differs from the “T- B+ NK-” pattern of the more common X-linked SCID, but it is not so well differentiated from “T- B-” patterns found in SCID caused by mutation of RAG1, RAG2, DCLRE1C, PRKDC, NHEJ1, and AK2 [Buckley 2004, Fischer et al 2005].

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, 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.

Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

Management

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with adenosine deaminase (ADA) deficiency, the following evaluations are recommended:

  • Identification of specific disease-causing viral, fungal, or bacterial organisms (both normal pathogens and opportunistic agents)
  • Complete blood count (CBC)
  • Flow cytometry to quantify lymphocyte subsets (T-, B-, NK-cells)
  • Assessment of humoral immune function by measuring serum immunoglobulins and the titer of specific antibodies related to infections and immunizations
  • Evaluation of cellular immune function by in vitro response of blood mononuclear cells to mitogens and antigens
  • Measurement of erythrocyte dAXP concentration to evaluate metabolic severity
  • Liver function testing to assess for metabolic hepatitis
  • Auditory testing
  • Other testing as indicated by clinical manifestations
  • Medical genetics consultation

Treatment of Manifestations

The following are appropriate:

  • Treatment of infections with specific antibiotic, antifungal, and antiviral agents
  • Prophylaxis for Pneumocystis jiroveci
  • Intravenous immunoglobulin (IVIg)

Prevention of Primary Manifestations

Restoring a functional immune system is essential and can be achieved in several ways. The choice of therapy is complex and depends on a number of factors, including the patient's age and clinical status, the expectations and desires of the parents, and the specific experience and expertise of physicians in treating ADA-deficient SCID. The experience with treatment of individuals with ADA deficiency was the subject of workshop in 2006 [Booth et al 2007]. A second workshop held in 2008 developed consensus guidelines for therapy [Gaspar et al 2009 (full text)].

For nearly three decades the method of choice for treating all forms of SCID has been bone marrow/stem cell transplantation (BMT/SCT) from an HLA-identical healthy sibling [Buckley et al 1999, Gaspar 2010]. This can be performed without cytoreductive conditioning of the patient, and without depletion of donor T-cells. Results vary among transplant centers, but the procedure is curative in approximately 70% or more of affected individuals. The main risks are graft-versus-host disease and delayed or incomplete recovery of humoral immune function, requiring continued treatment with IVIg.

For the majority of individuals with ADA-deficient SCID who lack an HLA-identical related donor, two other forms of treatment, which have been available for more than two decades, can be considered [Gaspar et al 2009, Gaspar 2010, Candotti et al 2012]:

  • BMT/SCT from a “non-ideal” donor (HLA-matched, unrelated; HLA-haploidentical parent; umbilical cord blood)
  • Enzyme replacement therapy (ERT) with polyethylene glycol-modified bovine adenosine deaminase (PEG-ADA, Adagen®)

The status of gene therapy is discussed in Therapies Under Investigation.

BMT/SCT from a “non-ideal” donor. Donor-derived T-cells are depleted to minimize the risk of graft-versus-host disease. Pre-transplant cytoreductive “conditioning” of the recipient (patient with SCID) is often performed to prevent graft loss, which occurs with relative frequency in patients with ADA-deficient SCID who are not conditioned. Some transplant centers do not perform conditioning of the recipient prior to a haploidentical transplant because of the risk of peri-transplant morbidity [Buckley et al 1999]. However, this latter approach has frequently been associated with a failure to achieve stable engraftment [Gaspar et al 2009, Gaspar 2010, Hassan et al 2012].

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 therapy with IVIg.

Universal agreement regarding the best methods for performing partially mismatched BMT/SCT does not exist [Cancrini et al 2010, Gaspar 2010, Hassan et al 2012]. 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.

In addition to differences in methodology, evaluation of results with partially mismatched BMT/SCT is difficult because ADA deficiency accounts for only approximately 15% of SCID. Nevertheless, available data indicate greater morbidity and mortality after pre-transplant conditioning among patients with ADA deficiency than among those with other forms of SCID [Haddad et al 1998, Antoine et al 2003, Grunebaum et al 2006, Gaspar 2010, Hassan et al 2012]. Survival beyond two to three years post-transplant has ranged from below 50% to approximately 65%. Individuals with ADA-deficient SCID may also be more likely to develop various neurologic abnormalities as a late complication after BMT/SCT, regardless of the HLA compatibility of the donor and recipient [Rogers et al 2001, Grunebaum et al 2006, Hönig et al 2007]. This is an area of ongoing interest.

Enzyme replacement therapy (ERT). PEG-ADA is composed of purified bovine ADA covalently linked to multiple strands of PEG (average mass: 5 kd) in order to prolong circulating life and reduce immunogenicity. It is administered by intramuscular injection once or twice a week (~15-60 U/kg per week). By maintaining a high level of ADA activity in plasma, PEG-ADA eliminates extracellular Ado and dAdo, preventing the toxic metabolic effects that interfere with lymphocyte viability and function and that may injure other organs (liver, lung, brain) [Hershfield et al 1987, Hershfield & Mitchell 2001, Hershfield 2004, Gaspar et al 2009].

ERT is not curative; PEG-ADA must be given regularly and at a sufficient dose to maintain a non-toxic metabolic environment.

PEG-ADA has been used as a primary therapy in individuals who lack an HLA-identical marrow/stem cell donor when the risks associated with a partially mismatched transplant are deemed too great or when the risk of graft failure is high, as in older individuals with a delayed- or late-onset phenotype. PEG-ADA has also been used as a secondary therapy in patients who have failed to engraft following an unconditioned BMT/SCT, or in whom an acceptable recovery of immune function has not been achieved following experimental gene therapy.

Most individuals treated with PEG-ADA recover partial immune function that is sufficient to prevent opportunistic infections and other clinical manifestations of SCID. As with T cell-depleted BMT/SCT, a lag of approximately two to four months occurs before T-cell function appears, but B-cells often increase earlier than after BMT/SCT. 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 2005, Malacarne et al 2005, Serana et al 2010, Brigida et al 2014]. Approximately half of those maintained on ERT continue to receive IVIg.

PEG-ADA received FDA approval in 1990. As of April 2014 more than 250 affected individuals have received PEG-ADA. When reviewed in April 2006, of more than 150 affected individuals who had ever begun ERT with PEG-ADA, approximately 90 were then still under treatment [Hershfield 2004, Gaspar et al 2009]. Survival of PEG-ADA-treated individuals beyond five years and through approximately ten years was 75%-80%, comparable or superior to that achieved with BMT/SCT. 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. Several late deaths (beyond two years of treatment) resulted from progression of chronic pulmonary insufficiency that was present at the time ERT was begun.

As of the present, lymphoproliferative disorders have developed in eight individuals who received PEG-ADA for eight to 22 years [Hershfield 2004, Chan et al 2005, Kaufman et al 2005, Husain et al 2007, and 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 2.5 years of ERT; the tumor was thought to have been present but undetected prior to ERT. 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 2004, Lainka et al 2005].

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.e., beyond 10-15 years) decline to an inadequate level. Approximately 20% of patients have discontinued ERT in order to undergo BMT/SCT. 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 patient 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 2004, Gaspar et al 2009].

Most individuals treated with PEG-ADA for longer than a year develop antibodies that bind specifically to bovine ADA and are detectable by an enzyme-linked immunosorbent assay (ELISA); these are of no clinical significance. Neutralizing antibodies that inhibit catalytic activity and enhance clearance of PEG-ADA (and which do compromise efficacy) have developed in fewer than 10% of treated individuals [Chaffee et al 1992, Hershfield 1997]. No allergic or hypersensitivity reactions to PEG-ADA have occurred, and the treatment has generally been well tolerated.

Prevention of Secondary Complications

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.

Surveillance

Annual or more frequent evaluation of lymphocyte counts, serum immunoglobulin levels, and various in vitro tests of cellular and humoral immune function (i.e., as listed above for the evaluation of individuals suspected of having SCID) should be performed following BMT/SCT and during ERT [Gaspar et al 2009].

Individuals on ERT also require periodic monitoring as follows:

  • Plasma levels of PEG-ADA activity
  • Erythrocyte dAXP concentration
  • Development of neutralizing antibodies, particularly if plasma ADA activity or clinical or immunologic status declines unexpectedly
  • The appearance or recurrence of dermatofibrosarcoma protuberans (DFSP)

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.

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

Experimental gene therapy for ADA-deficient SCID employing gamma retroviral vectors has been under clinical investigation for more than 20 years [Engel et al 2003, Cavazzana-Calvo et al 2005]. Clinical trials since about 2000 have employed an approach that was first reported for two patients treated in Milan, Italy and has recently been updated for ten patients [Aiuti et al 2002, Aiuti et al 2009]. This involves discontinuing PEG-ADA (in patients receiving ERT) and administering non-myeloablative conditioning prior to the infusion of ADA vector-transduced autologous CD34+ stem cells. In addition to the Milan study, variations on this protocol are currently under investigation in the UK, US, and Japan. More than 40 affected individuals (most of whom had been receiving PEG-ADA) have been treated at these centers [Aiuti et al 2002, Gaspar et al 2006, Engel et al 2007, Aiuti et al 2009, Cappelli & Aiuti 2010, Candotti et al 2012, Gaspar et al 2013]. At this time no deaths have been reported. Reconstitution of immune function is generally slow and may take a year or more. In most (but not all) affected individuals stable ADA expression in lymphoid cells has been achieved, along with correction of metabolic abnormalities in erythrocytes, which has resulted in maintenance of good health without the need for ERT. In contrast to the experience with gene therapy for X-linked SCID, no patients with ADA deficiency have thus far developed leukemia as a result of vector-associated insertional mutagenesis following gene therapy [Aiuti et al 2007, Cappelli & Aiuti 2010]. However, because of this concern and in order to achieve more effective ADA expression, clinical investigation of gene therapy using lentiviral vectors has now begun [Farinelli et al 2014].

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Adenosine deaminase (ADA) deficiency is inherited in an autosomal recessive manner.

Risk to Family Members

Parents of a proband

  • The parents of an affected child are obligate heterozygotes and therefore carry one mutant allele.
  • Heterozygotes (carriers) are asymptomatic.

Sibs of a proband

  • 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.
  • Once an at-risk sib is known to be unaffected (i.e., immunocompetent), the risk of his/her being a carrier is 2/3.
  • Heterozygotes (carriers) are asymptomatic.

Offspring of a proband. The offspring of an individual with ADA deficiency are expected to be obligate heterozygotes (carriers) for a pathogenic variant in ADA.

Other family members of a proband. Each sib of the proband's parents is at a 50% risk of being a carrier.

Carrier Detection

Molecular genetic testing. Carrier testing for at-risk family members is possible once the pathogenic variants have been identified in the family.

Biochemical testing. Measurement of ADA activity in erythrocytes has been used to identify heterozygotes. However, as there is some overlap between the erythrocyte ADA activity in heterozygotes and the lower end of the normal range, the results of biochemical testing should be interpreted with caution.

Related Genetic Counseling Issues

See Management, Evaluation of Relatives at Risk for information on evaluating at-risk relatives for the purpose of early diagnosis and treatment.

Family planning

  • The optimal time for determination of genetic risk, clarification of carrier status, and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected, are carriers, or are at risk of being carriers.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, allelic variants, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Biochemical testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of ADA activity in cultured amniotic fibroblasts or cultured chorionic villi cells grown from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation).

Molecular genetic testing. If the pathogenic variants have been identified in an affected family member, prenatal testing for pregnancies at increased risk may be available from a clinical laboratory that offers either testing for this disease/gene or custom prenatal testing.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the pathogenic variants have been identified.

Resources

GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Canadian Immunodeficiencies Patient Organization (CIPO)
    362 Concession Road 12
    RR #2
    Hastings Ontario K0L 1Y0
    Canada
    Phone: 877-262-2476 (toll-free)
    Fax: 866-942-7651 (toll-free)
    Email: info@cipo.ca
  • Immune Deficiency Foundation (IDF)
    40 West Chesapeake Avenue
    Suite 308
    Towson MD 21204
    Phone: 800-296-4433 (toll-free)
    Email: idf@primaryimmune.org
  • International Patient Organisation for Primary Immunodeficiencies (IPOPI)
    Firside
    Main Road
    Downderry Cornwall PL11 3LE
    United Kingdom
    Phone: +44 01503 250 668
    Fax: +44 01503 250 668
    Email: info@ipopi.org
  • Jeffrey Modell Foundation/National Primary Immunodeficiency Resource Center
    747 Third Avenue
    New York NY 10017
    Phone: 866-463-6474 (toll-free); 212-819-0200
    Fax: 212-764-4180
    Email: info@jmfworld.org
  • National Human Genome Research Institute (NHGRI)
  • NCBI Genes and Disease
  • Purine Research Society
    5424 Beech Avenue
    Bethesda MD 20814-1730
    Phone: 301-530-0354
    Fax: 301-564-9597
    Email: purine@erols.com
  • European Society for Immunodeficiencies (ESID) Registry
    Dr. Gerhard Kindle
    University Medical Center Freiburg Centre of Chronic Immunodeficiency
    UFK, Hugstetter Strasse 55
    79106 Freiburg
    Germany
    Phone: 49-761-270-34450
    Email: registry@esid.org
  • RDCRN Patient Contact Registry: Primary Immune Deficiency Treatment Consortium

Molecular Genetics

Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.

Table A. Adenosine Deaminase Deficiency: Genes and Databases

Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.

Table B. OMIM Entries for Adenosine Deaminase Deficiency (View All in OMIM)

102700SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY
608958ADENOSINE DEAMINASE; ADA

Gene structure. ADA spans 32,040 bp and comprises 12 exons. For a detailed summary of gene and protein information, see Table A, Gene Symbol.

Benign allelic variants. Two polymorphisms that do not significantly reduce ADA activity are known: p.Asp8Asn and p.Lys80Arg [Hirschhorn 1999, Hershfield & Mitchell 2001].

Table 2. ADA Benign Variants Discussed in This GeneReview

DNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequences
c.22G>Ap.Asp8AsnNM_000022​.2
NP_000013​.2
c.239A>Gp.Lys80Arg

Note on variant classification: Variants listed in the table have been provided by the author. GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

Pathogenic allelic variants. More than 70 ADA pathogenic variants have been identified in individuals with adenosine deaminase (ADA) deficiency with immunodeficiency or in healthy individuals with “partial ADA deficiency” [Hirschhorn 1999, Hershfield & Mitchell 2001, Vihinen et al 2001]. The distribution is approximately 60% missense, 20% splicing, 9% intra-exonic deletion, 7% nonsense, and 3% deletion of one or multiple exons (see Table A).

Normal gene product. ADA, the ADA gene product, has a mass of 41 kd and is active as a monomer; a tightly bound zinc ion is essential for catalytic activity [Wang & Quiocho 1998]. ADA is located in the cytoplasm in red cells and most lymphocytes. In addition to its location in the cytoplasm, another form of ADA, known as ADA-binding protein, exists as an “ecto” form that is bound to the plasma membrane glycoprotein D26/dipeptidylpeptidase IV (DPPIV) on fibroblasts, on some activated T-cells and medullary thymocytes, and on many epithelial cells. The function of ADA and the consequences of ADA deficiency have been reviewed [Hershfield & Mitchell 2001]. ADA serves a housekeeping role in the metabolic interconversion of purine nucleosides in all cells. In lymphoid cells, ADA serves an essential detoxifying function by eliminating dAdo in order to prevent dATP pool expansion, which interferes with DNA replication and promotes apoptosis. “Ecto-ADA” may modulate Ado-mediated signal transduction by controlling the extracellular concentration of Ado.

Abnormal gene product. A few ADA missense mutations found in individuals with SCID directly alter substrate or zinc cofactor binding, but most are distant from the active site and result in very unstable proteins. An ADA pathogenic variant that has a minor effect on catalytic activity but strongly interferes with binding to CD26/DPPIV has been identified in a healthy adult whose second ADA allele had a nonsense mutation [Richard et al 2000]. This finding, combined with the observation that in mouse, ADA does not bind to CD26/DPPIV, suggests that “ecto ADA” is not essential for immune function.

References

Published Guidelines/Consensus Statements

  1. Gaspar HB, Aiuti A, Porta F, Candotti F, Hershfield MS, Notarangelo LD. How I treat ADA deficiency. Available online. 2009. Accessed 6-16-14.

Literature Cited

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Suggested Reading

  1. Hershfield MS. Genotype is an important determinant of phenotype in adenosine deaminase deficiency. Curr Opin Immunol. 2003;15:571–7. [PubMed: 14499267]
  2. Hershfield MS, Mitchell BS. Immunodeficiency diseases caused by adenosine deaminase deficiency and purine nucleoside phosphorylase deficiency. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B, eds. The Online Metabolic and Molecular Bases of Inherited Disease (OMMBID). New York, NY: McGraw-Hill. Chap 109. Available online. 2014. Accessed 6-16-14.
  3. Nyhan WL. Disorders of purine and pyrimidine metabolism. Mol Genet Metab. 2005;86:25–33. [PubMed: 16176880]

Chapter Notes

Revision History

  • 19 June 2014 (me) Comprehensive update posted live
  • 22 December 2011 (me) Comprehensive update posted live
  • 14 July 2009 (cd) Revision: deletion/duplication analysis available clinically
  • 28 April 2009 (et) Comprehensive update posted live
  • 3 October 2006 (me) Review posted to live Web site
  • 24 April 2006 (mh) Original submission
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