Severe combined immunodeficiency due to adenosine deaminase deficiency
General Information (adopted from Orphanet):
Synonyms, Signs:
ADA-SCID
SCID due to ADA deficiency, early-onset SCID due to ada deficiency, delayed onset, included
SCID due to ADA deficiency
SCID due to adenosine deaminase deficiency
Adenosine deaminase deficiency, partial, included
SCID due to ADA deficiency, late-onset, included
Partial ADA deficiency, included
ADA deficiency
Hirschhorn et al. (1975) diagnosed ADA deficiency in a fetus by finding less than 1.5% ADA activity in cultured amniotic fluid cells. An older sib had died from SCID due to ADA deficiency. ...- Prenatal Diagnosis Hirschhorn et al. (1975) diagnosed ADA deficiency in a fetus by finding less than 1.5% ADA activity in cultured amniotic fluid cells. An older sib had died from SCID due to ADA deficiency. Aitken et al. (1980) used a microradioassay to evaluate ADA activity in cultured amniotic fluid cells in a pregnancy at risk for ADA deficiency and SCID. A low-normal level of activity consistent with the heterozygous state was found in the fetus, which was confirmed after birth. In 2 subsequent pregnancies of a mother of a child with SCID due to ADA deficiency, Ziegler et al. (1981) assayed ADA activity in amniotic fluid fibroblasts and diagnosed a normal fetus and a homozygous ADA-deficient fetus, respectively. The diagnoses were confirmed after birth and in abortus tissue
Inherited ADA deficiency causes a variable phenotypic spectrum, the most severe being SCID presenting in infancy and usually resulting in early death. Ten to 15% of patients have a 'delayed' clinical onset by age 6 to 24 months, and ...Inherited ADA deficiency causes a variable phenotypic spectrum, the most severe being SCID presenting in infancy and usually resulting in early death. Ten to 15% of patients have a 'delayed' clinical onset by age 6 to 24 months, and a smaller percentage of patients have 'later' onset, diagnosed from ages 4 years to adulthood, showing less severe infections and gradual immunologic deterioration. Finally, 'partial' ADA deficiency occurs in a subset of immunocompetent individuals who show decreased enzyme activity in erythrocytes, but retain substantial enzyme activity ranging from 5 to 80% of normal in leukocytes and other nucleated cells (Arredondo-Vega et al., 1994). ADA deficiency accounts for approximately 15% of all SCID cases and one-third of cases of autosomal recessive SCID (Hershfield, 2003). - Early Onset Giblett et al. (1972) reported 2 unrelated girls with impaired cellular immunity and absence of red cell adenosine deaminase activity. One child, aged 22 months, had recurrent respiratory infections, candidiasis, and marked lymphopenia from birth. The other, aged 3.5 years, was allegedly normal in the first 2 years of life. Mild upper respiratory infections began at age 24 months and progressed to severe pulmonary insufficiency and hepatosplenomegaly by age 30 months. The parents of the first child were related and the second child had a sister who died as a result of a major immunologic defect (Hong et al., 1970). The finding that both pairs of parents had an intermediate level of red cell ADA supported recessive inheritance; the parents of the first child had about a 50% level of normal, whereas the parents of the second child had about a 66% level. Parkman et al. (1975) reported 3 affected infants from 2 families with SCID due to ADA deficiency inherited in an autosomal recessive pattern. None of the infants had detectable erythrocyte ADA activity. Two infants had successful bone marrow transplantation with restoration of normal cellular and humoral immunity, but erythrocytic ADA deficiency persisted. Reporting on a workshop on SCID due to ADA deficiency, Meuwissen et al. (1975) noted that the phenotype is transmitted as an autosomal recessive disorder. Some patients had characteristic skeletal abnormalities, and all had thymic involution with Hassall's corpuscles and differentiated germinal epithelium. Hershfield (2003) stated that red cell 2-prime-deoxyadenosine triphosphate (dATP; dAXP), a substrate of adenosine deaminase, is elevated by 30-fold to greater than 1,500-fold in SCID patients. - Delayed or Late Onset Santisteban et al. (1993) reported 7 patients with 'delayed' or 'late' onset of SCID due to ADA deficiency. Three of these patients had onset of symptoms at ages 9, 12, and 12 months, respectively, although diagnosis of ADA deficiency was not made until ages 14 months, 2, and 3 years, respectively. Four patients were relatively asymptomatic until ages 2 to 5 years, when recurrent respiratory infections became prominent. ADA activity in cultured T cells and deoxyadenosine nucleotide levels in red cells in all 7 patients were intermediate between typical early-onset SCID patients and immunocompetent individuals with partial ADA deficiency. Umetsu et al. (1994) reported 2 sisters with SCID due to ADA deficiency. The second-born child presented first with serious infections and failure to thrive at age 4 months; the diagnosis of SCID was made at age 9 months when the child was hospitalized for Pseudomonas sepsis and Pneumocystis pneumonia. Her healthy 39-month-old sister was then tested and found to be ADA deficient. She had an unremarkable history, including normal development and uncomplicated varicella zoster at age 6 months. Although she was lymphopenic, antibody production, delayed hypersensitivity, and in vitro T-cell function were intact. She became more lymphopenic over a period of 6 to 7 months and developed persistent upper respiratory infections. Both sisters were treated by enzyme replacement with polyethylene glycol (PEG)-ADA. Shovlin et al. (1993) described adult onset of ADA deficiency in 2 sisters who presented with recurrent infections together with laboratory phenotypes similar to those of advanced HIV disease, including severe CD4 lymphopenia. Both were HIV-negative. A 34-year-old woman reported asthma and recurrent chest infections from childhood. As an adult, she had widespread viral warts, recurrent oral and vaginal candidosis, and reported 2 episodes of dermatomal zoster. Her 35-year-old sister was well until age 17 when she developed idiopathic thrombocytopenic purpura necessitating splenectomy, azathioprine for 7 years, and prednisolone until the time of report. By age 20 she had asthma, recurrent chest infections, vaginal and oral candidosis, widespread viral warts, and recurrent dermatomal zoster. Both sisters had clinical and radiologic evidence of extensive lung damage. Medical records showed lymphopenia in both sisters from ages 20 and 17 years, respectively. These were the oldest patients ever described with a new diagnosis of primary ADA deficiency. Ozsahin et al. (1997) reported metabolic, immunologic, and genetic findings in 2 ADA-deficient adults with distinct phenotypes. A 39-year-old woman had combined immunodeficiency with frequent infections, lymphopenia, and recurrent hepatitis as a child, but did relatively well in her second and third decades. She later developed chronic sinopulmonary infections, including tuberculosis, and hepatobiliary disease, and died of viral leukoencephalopathy at 40 years of age. The second patient was a healthy 28-year-old man with normal immune function who was identified after his niece died of SCID. Both adult patients lacked erythrocyte ADA activity, but had only modestly elevated deoxyadenosine nucleotides. Hershfield (2003) stated that red cell dATP (dAXP) is elevated by 30- to 300-fold in delayed or late-onset patients. - Partial ADA Deficiency Jenkins (1973) and Jenkins et al. (1976) reported a South African Kalahari San ('Bushman') patient with 'partial' ADA deficiency not associated with immunodeficiency. ADA activity was 2 to 3%, 10 to 12%, and 10 to 30% of normal in red blood cells, white blood cells, and fibroblasts, respectively. Multiple tests showed that the child had normal humoral and cellular immunity. A sib had similar ADA levels and the parents had intermediate levels. In a study of 36 South African populations comprising more than 3,000 individuals, Jenkins et al. (1976) found that many members of the Kung Bushman population had red cell ADA deficiency not associated with immunodeficiency. The authors concluded that the phenotype was due to a polymorphic allele, designated ADA-8, with a frequency of approximately 0.11 in the Kung population. Hart et al. (1986) reported a second Bantu-speaking Xhosa man from South Africa with partial ADA deficiency similar to the type previously reported by Jenkins et al. (1976). Erythrocyte ADA levels were decreased at 6 to 9% of normal, whereas white cell ADA was approximately 30% of normal, and the enzyme showed decreased stability in vitro. Levels of dATP were 2- to 3-fold above normal in red blood cells. Electrophoretic studies suggested compound heterozygosity. Hirschhorn et al. (1979) reported a patient with ADA deficiency without immunodeficiency in whom the mutant ADA enzyme was unstable. Daddona et al. (1983) reported another patient with partial ADA deficiency and normal immune function. ADA activity and protein were undetectable in red blood cells, 0.9% of normal in lymphocytes, 4% in lymphoblasts, and 14% in fibroblasts. The ADA protein was abnormally acidic. Hirschhorn et al. (1983) reported 4 unrelated children with partial ADA deficiency who lacked ADA in their erythrocytes but retained variable amounts of activity in their lymphoid cells. None had significant immunologic deficiency. Electrophoretic mobility studies showed different forms of the enzyme: one form was acidic, had very low activity, and was heat-stable; a second was basic, had low activity, and was heat-labile; a third was heat-labile and retained relatively normal activity; and a fourth had decreased activity without qualitative abnormalities. Hirschhorn et al. (1983) concluded that 3 of the individuals had mutations at the structural locus for ADA, and that the fourth may have had a mutation at a regulatory locus. Noting that 2 of the partially deficient families were of African descent and a third came from the Mediterranean basin, Hirschhorn et al. (1983) suggested that partial ADA deficiency may confer an advantage against intraerythrocytic parasites, such as malaria or babesiosis, which require exogenous purines derived from the host to survive. Hirschhorn and Ellenbogen (1986) reported 5 unrelated patients with partial ADA deficiency identified through a New York state neonatal screening program. None of them had immunologic abnormalities. Three patients were shown to be genetic compounds by the presence of 2 electrophoretically distinguishable allozymes or by family studies that demonstrated a null allele in addition to an electrophoretically abnormal enzyme. All 5 of the children were either black or of West Indian descent, suggesting a clustering of the partial ADA deficiency phenotype in this ethnic group. The genetically distinct enzymes excluded a founder effect, and the authors again concluded a selective advantage for partial ADA deficiency. Hershfield (2003) stated that red cell dATP (dAXP) is elevated by zero to approximately 30-fold in patients with partial ADA deficiency
Hirschhorn et al. (1994) reported a patient diagnosed with SCID due to ADA deficiency at age 2.5 years because of life-threatening pneumonia, recurrent infections, failure of normal growth, and lymphopenia. However, he retained significant cellular immune function. His condition ...Hirschhorn et al. (1994) reported a patient diagnosed with SCID due to ADA deficiency at age 2.5 years because of life-threatening pneumonia, recurrent infections, failure of normal growth, and lymphopenia. However, he retained significant cellular immune function. His condition improved dramatically in the absence of specific therapy, and he was a healthy adolescent at age 16 years with no medical problems at age 20 years. A fibroblast cell line and a B-cell line, established at the time of diagnosis, lacked ADA activity. Genetic analysis identified compound heterozygosity for a splice site mutation (608958.0024) and a missense mutation (608958.0003). All clones isolated from the B-cell mRNA carried the missense mutation, indicating that the allele with the splice site mutation produced unstable mRNA. In striking contrast, a B-cell line established at age 16 expressed 50% of normal ADA; 50% of ADA mRNA had normal sequence, and 50% had the missense mutation. Genomic DNA contained the missense mutation, but not the splice site mutation. Genomic DNA from peripheral blood cells obtained at 16 years of age indicated in vivo somatic mosaicism; less than half the DNA carried the splice site mutation (P less than 0.002, vs original B-cell line). Consistent with the mosaicism, erythrocyte content of the toxic metabolite deoxy-ATP was only minimally elevated. Hirschhorn et al. (1994) postulated that somatic mosaicism could have arisen by somatic mutation or by reversion at the site of mutation. Selection in vivo for ADA normal hematopoietic cells likely played a role in the return to normal health in the absence of therapy. Hirschhorn et al. (1996) reported a patient who presented during the first years of life with recurrent infections and lymphopenia. A prior sib died before age 3 years of SCID affecting both T and B cells. At age 5 years, the proband lacked ADA activity in erythrocytes, but concentrations of deoxy-ATP in red blood cells were only mildly elevated compared to concentrations found in severe SCID patients. Mononuclear cells had 15% of normal ADA activity. Both the mother and father had 50% and 20 to 25% normal activity in erythrocytes and lymphocytes, respectively. Between the ages of 8 and 12 years, the proband was clinically healthy, with normal growth and development, although he had persistent hyper-IgE, decreased numbers of CD4+ T cells and B cells, and increased numbers of CD8+ T cells. Genetic analysis identified compound heterozygosity for 2 mutations in the ADA gene: a splice site mutation (608958.0026), inherited from the father, and an R156H mutation (608958.0032) inherited from the mother. Peripheral blood from the proband at age 11 years showed the splice site and R156H mutations in 50% and 34%, respectively, of cells, whereas 17% of cells did not carry either mutation. Cell lines established showed virtual absence of the maternally derived R156H mutation, indicating in vivo reversion of the mutation to normal. A similar moderation of phenotype had been observed involving a revertant mutation in the IL2RG gene (308380) in X-linked SCID (300400) (Stephan et al., 1996). Revertant cells have also been identified in patients with Fanconi anemia (see 227650 and 227645), Bloom syndrome (210900), Wiskott-Aldrich syndrome (277970), and epidermolysis bullosa (226650) due to mutations in the COL17A1 gene (113811). In addition to back mutation, allele function has been restored by mitotic recombination or gene conversion, which can eliminate the original mutation, and by 'second-site' events that restore reading frame or led to an amino acid substitution better tolerated than the original. In Bloom syndrome, intragenic recombination or gene conversion are the usual mechanisms, consistent with reversion being much more common in heteroallelic than in homoallelic patients (Ellis et al., 1995). Arredondo-Vega et al. (2002) reported 1 member of a Saudi Arabian family with delayed onset of SCID due to a homozygous splice site mutation in the ADA gene (608958.0030) who also carried an acquired second distinct splice site mutation (608958.0031) that suppressed the defect of the first mutation. The patient had a milder phenotype than his sister who did not carry the second mutation. Arredondo-Vega et al. (1998) noted that the phenotype of ADA deficiency is strongly associated with the sum of ADA activity provided by both alleles. Many mutations are private and patients are often heteroallelic, precluding definite genotype/phenotype correlations. Functional expression analysis of 29 different missense mutations expressed in an ADA-deleted E. coli strain showed that alleles from immunodeficient patients expressed 0.001 to 0.6% ADA activity compared to wildtype. Alleles found only in healthy individuals with partial deficiency showed 1 to 28% of normal activity. In all, the activity levels spanned 5 orders of magnitude. The authors found that 1 to 1.5% residual ADA activity was consistent with sustaining immune function. There was a strong inverse correlation between red cell dAXP concentration and the sum of ADA activity expressed by both alleles, establishing a direct link between the effects of genotype on residual ADA activity, metabolism, and clinical expression
- Severe Combined Immunodeficiency due to ADA Deficiency
In a patient with SCID due to ADA deficiency who was originally reported by Hirschhorn et al. (1975), Valerio et al. (1986) identified compound heterozygosity for 2 mutations in ...- Severe Combined Immunodeficiency due to ADA Deficiency In a patient with SCID due to ADA deficiency who was originally reported by Hirschhorn et al. (1975), Valerio et al. (1986) identified compound heterozygosity for 2 mutations in the ADA gene (608958.0001; 608958.0005). Akeson et al. (1987) reported several mutation in the ADA gene in patients with ADA-deficient SCID (see, e.g., 608958.0004; 608958.0006; 608958.0017). In 2 sisters with SCID due to ADA deficiency reported by Umetsu et al. (1994), Arredondo-Vega et al. (1994) identified compound heterozygosity for 2 splice site mutations in the ADA gene (608598.0022; 608598.0023). - Delayed or Late-Onset SCID In 7 patients with delayed or late onset of SCID due to ADA deficiency, Santisteban et al. (1993) identified mutations in the ADA gene (see, e.g., 608958.0020 and 608958.0032). - Partial ADA Deficiency In patients with partial ADA deficiency, Hirschhorn et al. (1989, 1990) identified several mutations in the ADA gene (608958.0009-608958.0015)
Diagnostic criteria for adenosine deaminase (ADA) deficiency:...
DiagnosisClinical DiagnosisDiagnostic criteria for adenosine deaminase (ADA) deficiency:Evidence of combined immunodeficiencyLess 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)TestingImmune functionLymphopenia, 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.Adenosine deaminase (ADA) catalytic activityAffected individuals who have not been transfused have less than 1% of normal ADA catalytic activity in erythrocyte hemolysates.Affected individuals who have been recently transfused may require testing of another cell type, such as fibroblasts or leukocytes.Note: (1) Both spectrophotometric and radiochemical methods have been used to assay ADA catalytic activity [Hershfield & Mitchell 2001]. (2) Analysis of plasma is not useful for diagnosis because ADA catalytic activity is much lower in plasma than in cells, even in controls, and because plasma contains a nonspecific "ADA-like" activity not derived from ADA.Biochemical markers of ADA deficiency. The inability to deaminate 2'-deoxyadenosine (dAdo) results in specific metabolic abnormalities in erythrocytes and urine of affected individuals. These markers may help to confirm the diagnosis and to monitor therapies intended to restore ADA function:Elevated erythrocyte dAdo nucleotides (dAXP). Normal red cells lack dAXP, usually determined by high-pressure liquid chromatography (HPLC). ADA deficiency permits excessive dAdo phosphorylation, leading to a pathognomonic marked increase in total dAXP (mainly dATP) levels in red cells. If the affected individual has not been transfused, the level of dAXP correlates with clinical phenotype (ADA-deficient SCID > "delayed/late" onset > "partial ADA deficiency") and can be used in monitoring the biochemical effectiveness of therapy.Reduced erythrocyte S-adenosylhomocysteine hydrolase (AdoHcyase, SAHase) activity. Owing to inactivation by dAdo, AdoHcyase (SAHase) activity is less than 5% of normal.Urinary dAdo. Excretion of dAdo, usually measured by HPLC, is markedly elevated in individuals with ADA-deficient SCID.Molecular Genetic TestingGene. ADA is the only gene in which mutations cause ADA deficiency.Clinical testingSequence analysis. Sequence analysis of ADA (exons and intron/exon boundaries) can identify most known mutations, except for large deletions.Deletion/duplication analysis. Deletion/duplication analysis can detect partial- or whole-gene deletions, which represent a small, but unknown, fraction of the mutations responsible for ADA deficiency (see Table A. Genes and Databases, HGMD).Table 1. Summary of Molecular Genetic Testing Used in Adenosine Deaminase DeficiencyView in own windowGene SymbolTest MethodMutations DetectedMutation Detection Frequency by Test Method 1Test AvailabilityADA Sequence analysisSequence variants 2>90% 3Clinical Duplication / deletion testing 4Partial- or whole-gene deletionsUnknown1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. In individuals with biochemically documented ADA deficiency4. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; a variety of methods including quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), or targeted chromosomal microarray analysis (gene/segment-specific) may be used. A full chromosomal microarray analysis that detects deletions/duplications across the genome may also include this gene/segment. 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).For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Databases and/or Pathologic allelic variants).Testing StrategyTo confirm/establish the diagnosis in a proband. Expeditious testing for ADA deficiency in individuals suspected of having SCID is critical both because such individuals are often seriously ill and in need of specific therapy by the time this diagnosis is considered, and because the therapeutic options for ADA deficiency are different from those for SCID caused by other molecular defects.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 dAXP in red cells 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. Sequence analysis should be performed first; if one or no mutations are identified, deletion/duplication analysis may be considered. Newborn screening for SCID, involving measurement of T-cell receptor excision circles (TRECs), is now performed in several states in the US and may be adopted by others. As about 15% of all SCID results from ADA deficiency, it would be appropriate to perform biochemical testing for ADA deficiency in any newborns identified by TREC screening.Carrier testing for at-risk relatives requires prior identification of the disease-causing mutations in the family. Note: Carriers are heterozygotes for this autosomal recessive disorder and are not at risk of developing the disorder. Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutations in the family.Genetically Related (Allelic) DisordersNo other phenotypes are associated with mutations in ADA.
Adenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development and function [Hirschhorn 1999, Hershfield & Mitchell 2001, Hershfield 2004]. The phenotype ranges from SCID in infants, to less severe "delayed/late" onset in older children and adults, to benign "partial ADA deficiency."...
Natural HistoryAdenosine deaminase (ADA) deficiency is a systemic purine metabolic disorder that primarily affects lymphocyte development and function [Hirschhorn 1999, Hershfield & Mitchell 2001, Hershfield 2004]. The phenotype ranges from SCID in infants, to less severe "delayed/late" onset in older children and adults, to benign "partial ADA deficiency."ADA-Deficient Severe Combined Immunodeficiency Disease (SCID)Infants with ADA-deficient SCID have 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 generally made within the first six months of life.The initial hospitalization is often for pneumonitis, which may result from viral infection or Pneumocystis jiroveci infection; however, a causative agent may not be identified. Persistent diarrhea, extensive dermatitis, and other life-threatening illnesses caused by opportunistic infections occur frequently.Physical findings include growth failure, the absence of lymphoid tissues (tonsils, lymph nodes), and effects of specific infections. Thymus shadow is absent on x-ray. Although similar clinically to other forms of SCID, ADA-deficient SCID may be accompanied by characteristic rib abnormalities (cupping and flaring of costochondral junctions) and a higher incidence of hepatic and various neurologic abnormalities.Other organ involvement. The manifestations of combined immune deficiency dominate the clinical presentation of ADA deficiency. In addition to markedly decreased lymphocyte counts, some individuals may show reduced levels of neutrophils and myeloid bone marrow abnormalities, such as myeloid dysplasia and bone marrow 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, 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 protuberasn (DFSP) has recently been identified in several individuals with ADA deficiency [Kesserwan et al 2011]. 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 DeficiencyApproximately 15%-20% of children with ADA deficiency have a "delayed" onset of clinical symptoms after age six months or during the first few years of life. Rarely, individuals are diagnosed in the second to fourth decades ("late/adult" onset). Infections in delayed- and late-onset types may initially be less severe than those in individuals with ADA-deficient 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 DeficiencyScreening 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 has been called "partial ADA deficiency."
Most known ADA mutations 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]. ...
Genotype-Phenotype CorrelationsMost known ADA mutations 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]. A good correlation has been established between the effect of mutations on ADA activity and both clinical and metabolic phenotype [Arredondo-Vega et al 1998]. In several individuals the relationship of genotype to phenotype was modulated by mosaicism in lymphoid cells for reversion of deleterious mutations [Hirschhorn et al 1994, Hirschhorn et al 1996, Ariga et al 2001a, Arredondo-Vega et al 2002, Liu et al 2008, Moncada-Vélez et al 2011].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 systemSplice-site mutations. A separate group, as a low level of normal splicing may result in variable levels of ADA activityPhenotype 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 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:Individual differences in "leakiness" of a splice-site mutation [Arredondo-Vega et al 1994]Mosaicism for reversion of a mutant allele in lymphoid cells [Arredondo-Vega et al 2002]The segregation of both severe and mild mutant alleles in a family [Santisteban et al 1995, Ozsahin et al 1997, Ariga et al 2001b]
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....
Differential DiagnosisPurine 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.In addition to ADA deficiency, SCID can also result from mutations in other genes [Buckley 2004, Fischer et al 2005]. 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 RAG1M, RAG2, and ARTEMIS [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 discriminates 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 , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).
To establish the extent of disease in an individual diagnosed with adenosine deaminase (ADA) deficiency, the following evaluations are recommended:...
ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease 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 immunizationsEvaluation of cellular immune function by in vitro response of blood mononuclear cells to mitogens and antigensMeasurement of erythrocyte dAXP concentration to evaluate metabolic severityLiver function testing to assess for metabolic hepatitisAuditory testingOther testing as indicated by clinical manifestationsGenetics consultationTreatment of ManifestationsThe following are appropriate:Treatment of infections with specific antibiotic, antifungal, and antiviral agentsProphylaxis for Pneumocystis jiroveciIntravenous immunoglobulin (IVIg)Prevention of Primary ManifestationsRestoring 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; click for full text]. For more than 20 years 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 15 years, can be considered [Gaspar et al 2009, Gaspar 2010]: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].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]. 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]. 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 lymphocytes gradually decline in number and display various functional abnormalities [Chan et al 2005, Malacarne et al 2005, Serana et al 2010]. Approximately half of those maintained on ERT continue to receive IVIg.PEG-ADA received FDA approval in 1990. As of April 2006, more than 150 individuals have been treated worldwide, and approximately 90 individuals were still under treatment. The outcome of PEG-ADA therapy through 2006 has been reviewed [Hershfield 2004, Gaspar et al 2009]. Survival of PEG-ADA-treated individuals beyond five years and through approximately ten years has been 75%-80%, comparable or superior to that achieved with BMT/SCT. Most deaths have 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) have been caused by progression of chronic pulmonary insufficiency that was present at the time ERT was begun. Lymphoproliferative disorders have developed in six individuals who were treated with PEG-ADA for eight to 22 years [Hershfield 2004, Chan et al 2005, Kaufman et al 2005, Husain et al 2007]. 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 ComplicationsAs noted under Treatment of Manifestations, patients 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.SurveillanceAnnual or more frequent evaluation of lymphocyte counts and in vitro tests of cellular and humoral immune function (i.e., as listed above for the evaluation of patients 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 activityErythrocyte dAXP concentrationDevelopment of neutralizing antibodies, particularly if plasma ADA activity or clinical or immunologic status declines unexpectedlyThe appearance or recurrence of dermatofibrosarcoma protuberans (DFSP)Agents/Circumstances to AvoidThe 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 patients who lack ADA, and would interfere with PEG-ADA.Evaluation of Relatives at RiskIn the newborn sibs of a proband, it is appropriate to either assay ADA catalytic activity or perform molecular genetic testing (if the family-specific disease-causing mutations 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 InvestigationExperimental gene therapy for ADA-deficient SCID employing 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. The total number of patients treated at these centers to date is approximately 35, most of whom had been receiving PEG-ADA [Aiuti et al 2002, Gaspar et al 2006, Engel et al 2007, Aiuti et al 2009, Cappelli & Aiuti 2010]. 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) patients 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]. Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.
Information in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED....
Molecular GeneticsInformation 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 DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDADA20q13.12Adenosine deaminaseResource of Asian Primary Immunodeficiency Diseases (RAPID) ADA homepage - Mendelian genesADAData 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) View in own window 102700SEVERE COMBINED IMMUNODEFICIENCY, AUTOSOMAL RECESSIVE, T CELL-NEGATIVE, B CELL-NEGATIVE, NK CELL-NEGATIVE, DUE TO ADENOSINE DEAMINASE DEFICIENCY 608958ADENOSINE DEAMINASE; ADANormal allelic variants. ADA spans 32,040 bp and comprises 12 exons. Two polymorphisms that do not significantly reduce ADA activity are known: p.Asp8Asn and p.Lys80Arg [Hirschhorn 1999, Hershfield & Mitchell 2001].Table 2. ADA Normal Allelic Variants Discussed in This GeneReviewView in own windowDNA Nucleotide ChangeProtein Amino Acid ChangeReference Sequencesc.22G>Ap.Asp8AsnNM_000022.2 NP_000013.2c.239A>Gp.Lys80ArgSee Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www.hgvs.org).Pathologic allelic variants. More than 70 ADA mutations 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 normal 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 mutation 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.