Severe Combined Immunodeficiency, Autosomal Recessive, T Cell-Negative, B Cell-Negative, Nk Cell-Negative, Due To Adenosine Deaminase Deficiency

A number sign (#) is used with this entry because T cell-negative (T-), B cell-negative (B-), natural killer cell-negative (NK-) severe combined immunodeficiency (SCID) is caused by homozygous or compound heterozygous mutation in the adenosine deaminase gene (ADA; 608958) on chromosome 20q13.

For a general phenotypic description and a discussion of genetic heterogeneity of autosomal recessive SCID, see 601457.

Clinical Features

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.

Other Features

Ratech et al. (1985) reported postmortem findings in 8 patients with SCID due to ADA deficiency. Seven patients had renal mesangial sclerosis, and 6 had adrenal cortical sclerosis. Tissue from vertebrae and costochondral junctions in 4 patients showed short growth plates with few proliferating and some hypertrophic chondrocytes. Two patients who had received bone marrow or enzyme infusions had milder changes. The authors concluded that disordered nucleoside metabolism due to absent ADA activity results in multisystem pathologic changes.

Bollinger et al. (1996) described a human neonate with ADA deficiency, confirmed by genetic analysis, who developed prolonged hyperbilirubinemia with hepatitis that resolved after the institution of ADA replacement therapy. Percutaneous liver biopsy showed early giant-cell transformation, with enlarged foamy hepatocytes and portal and lobular eosinophilic infiltrates.

Hirschhorn et al. (1980) referred to neurologic abnormalities that had been reported in 2 of 23 ADA-deficient patients and reported a third who showed improvement of these features with enzyme replacement by red cell infusion. Neurologic abnormalities included movement disorders, nystagmus, and sensorineural deafness. Rogers et al. (2001) evaluated the cognitive, behavioral, and neurodevelopmental function in 11 case-matched pairs of patients with ADA-SCID and non-ADA-deficient SCID, all of whom had undergone bone marrow transplantation. Cognitive ability was not significantly different between the 2 groups, but patients with ADA-SCID had a significant inverse correlation between dATP levels at diagnosis and IQ. Behavioral assessment showed that patients with ADA-SCID functioned in the pathologic range on all domains, whereas mean scores for the control group were within normal limits. Behavioral impairment in patients with ADA-SCID also showed a significant positive correlation with age.

Mapping

Koch and Shows (1980) showed that ADA deficiency in SCID segregated with chromosome 20 in interspecific somatic cell hybrids, suggesting that a structural gene mutation at the ADA locus was the primary cause of ADA-deficient SCID.

Pathogenesis

Mitchell et al. (1978) found that deoxyadenosine and deoxyguanosine were particularly toxic to T cells but not to B cells. Addition of deoxycytidine or dipyridamole prevented deoxyribonucleoside toxicity.

Boss et al. (1981) concluded that ecto-5-prime-nucleotidase deficiency is secondary to the primary defect of ADA. In cells from a patient with ADA-deficient SCID, Herbschleb-Voogt et al. (1983) found a deficiency of ADA activity and a comparable deficiency of ADA-specific cross-reacting material, indicating a decrease of the enzyme.

Cohen et al. (1978) observed greater than 50-fold elevations of 2-prime-deoxyadenosine triphosphate (dATP) in the erythrocytes of 3 SCID ADA-deficient patients, but not in the erythrocytes of an immunocompetent ADA-deficient patient or 2 unrelated immunodeficient patients with normal ADA. In vivo infusion of normal erythrocytes containing normal ADA activity in 2 SCID ADA-deficient patients resulted in a dramatic decrease in dATP and some clinical response. Cohen et al. (1978) concluded that deoxyadenosine is the toxic substrate in ADA deficiency, and that the toxic effect is mediated by dATP inhibition of ribonucleotide reductase (see, e.g., 180410), which is responsible for the reduction of all the purine and pyrimidine ribonucleotides to their respective 2-prime-deoxyribonucleotides, the necessary precursors for DNA synthesis. Immunodeficiency is the consequence of the particular sensitivity of immature lymphoid cells to the toxic effects of ADA substrates.

Van de Wiele et al. (2002) noted that most immature thymocytes undergo apoptosis as a result of lymphocyte selection in the thymus. Degradation of cell DNA and RNA by ADA generates adenosine and deoxyadenosine. Accumulation of these metabolites and their derivatives in ADA deficiency is lymphotoxic, resulting in reduced production of T cells. In addition, dATP inhibits ribonucleotide reductase, which is necessary for DNA synthesis, and dATP and adenosine inhibit S-adenosylhomocysteine hydrolase (SAHH; 180960), which is necessary for methylation reactions that are required for cell viability. In cell cultures (fetal thymic organ culture, FTOC) from a mouse model of ADA deficiency, van de Wiele et al. (2002) found that inhibition of adenosine kinase (102750) resulted in an increase in T-cell recovery, indicating that toxicity in ADA deficiency is due to a phosphorylated form of an ADA substrate and not adenosine or deoxyadenosine. Further studies suggested that inhibition of SAH or ribonucleotide reductase was not sufficient to cause toxicity. Van de Wiele et al. (2002) concluded that the mechanism of dATP toxicity involves dATP-induced cytochrome c release from mitochondria, which initiates the apoptotic cascade.

Apasov et al. (2001) found that Ada -/- mice had a pronounced decrease in the size and lymphocyte content of spleen, lymph nodes, and thymus at 3 weeks of age compared to wildtype mice. There was increased apoptosis of immature T cells in the thymi of mutant mice, but not in the peripheral lymphoid organs, indicating specific effects on developing T cells. In addition, mature CD4- and CD8-positive T cells from Ada -/- mice showed decreased T cell receptor (TCR; see 186880)-triggered activation in vivo and in vitro as a result of increased exogenous adenosine, to a lesser extent than in mature T cells of wildtype mice, indicating that adenosine can affect normal T cell activation. The nucleoside 2-prime-deoxyadenosine was directly cytotoxic to lymphocytes. Apasov et al. (2001) concluded that T-cell depletion in ADA-deficient SCID results from at least 2 mechanisms: intracellular toxicity of adenosine, dATP, and 2-prime-deoxyadenosine, and inhibition of T-cell signaling by elevated levels of adenosine.

Diagnosis

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.

Clinical Management

Enzyme Replacement Therapy

Polmar et al. (1976) reported successful treatment of a child with SCID due to ADA deficiency by 'enzyme replacement therapy' using frozen irradiated red blood cells with normal ADA activity. After treatment, a thymic shadow appeared radiographically, lymphocytic responses were demonstrated in vitro, and there was immunoglobulin synthesis. With infusions at 4-week intervals, the child remained free of infection for 17 months.

Ziegler et al. (1980) reported a patient with SCID due to ADA deficiency who was treated with ADA-positive red cell infusions. Although there was some resolution of interstitial pneumonitis and skeletal abnormalities, there was no evidence of immunologic reconstitution, and the patient died at age 17 months. The authors noted that severe cases of SCID due to ADA deficiency may not respond to exogenous enzyme therapy. Markert et al. (1987) reported 5 ADA-deficient patients who showed no lasting benefit from red blood cell transfusions.

Hershfield et al. (1987) reported successful treatment of 2 SCID ADA-deficient patients with polyethylene glycol-modified bovine intestinal ADA (PEG-ADA). The modified enzyme was rapidly absorbed after intramuscular injection and had a half-life in plasma of 48 to 72 hours. Weekly doses maintained plasma ADA activity at 2 to 3 times the level of red cell ADA in normal subjects, resulting in a decrease in toxic deoxyadenosine nucleotides to less than 0.5% of total adenine nucleotides. The activity of S-adenosylhomocysteine hydrolase, which is inactivated by deoxyadenosine, increased to normal in red cells and nucleated marrow cells. Neither toxic effects nor hypersensitivity reactions were observed. In vitro tests of cellular immune function of each patient showed marked improvement, together with an increase in T lymphocytes. Covalent attachment of polyethylene glycol to ADA blocked access to vulnerable sites on the surface of the protein, inhibiting clearance from the circulation, attack by degrading enzymes, binding of antibodies, and processing by antigen-presenting cells.

Levy et al. (1988) reported a child who developed symptoms of SCID due to ADA deficiency at age 3 years. She had 0.6% and 1% of normal ADA activity in erythrocytes and mononuclear cells, respectively. Weekly treatment with PEG-modified ADA was well tolerated and her T lymphocyte numbers and response to mitogens became normal.

In a review, Hershfield (1995) noted that PEG-ADA works in the plasma by degrading adenosine (Ado) and deoxyadenosine (dAdo), followed by rapid equilibration with intracellular concentrations via a plasma membrane nucleoside transporter. After approximately 2 months of treatment, lymphocyte counts increase and show a proliferative response to mitogens in vitro, a thymic shadow may appear, and patients often develop persistent antibody titers. Although immune function is not normal, serious opportunistic infections usually resolve. Development of anti-ADA antibodies rarely occurs. Hershfield (1995) noted that PEG-ADA treatment is indicated for patients who lack an HLA-identical bone marrow donor, but are at too high a risk for HLA-haploidentical marrow transplantation. Mortality with PEG-ADA is lower than that with haploidentical bone marrow transplantation.

Bone Marrow Transplantation

Bortin and Rimm (1977) reported on the characteristics and results of treatment in 69 patients with SCID due to various causes; 4 of 25 (16%) patients tested had ADA deficiency. The highest 6-month survival rate occurred in those who had undergone bone marrow transplant (BMT) from HLA genotypically identical donors. In surveying 18 of 80 SCID patients who survived bone marrow transplantation, Kenny and Hitzig (1979) found that 3 of the 18 patients had ADA deficiency.

Buckley et al. (1999) reported survival of 11 of 13 ADA-deficient patients who underwent bone marrow transplantation. Seven of 9 children who underwent haploidentical BMT were alive 1.6 to 15.6 years after transplantation, with hematopoietic chimerism demonstrable in 6. T-cell numbers and function improved approximately 3 to 4 months after transplantation; B-cell numbers and function improved to a lesser degree.

Molecular Genetics

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).

Genotype/Phenotype Correlations

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.

Animal Model

Abbott et al. (1986) presented evidence that 'wasted' (wst) in mice is caused by a mutation in the structural gene for ADA. As occurs in humans with ADA deficiency, wasted mice are immunodeficient, develop neurologic abnormalities, and die soon after weaning.

Unlike humans, mice that express no adenosine deaminase die perinatally of severe hepatocellular degeneration (Migchielsen et al., 1995; Wakamiya et al., 1995).

Blackburn et al. (1998) reported the use of a 2-stage genetic engineering strategy to generate ADA-deficient mice that retained many features associated with ADA deficiency in humans, including a combined immunodeficiency. Severe T- and B-cell lymphopenia was accompanied by a pronounced accumulation of 2-deoxyadenosine and dATP in the thymus and spleen, and a marked inhibition of S-adenosylhomocysteine hydrolase in the same organs. Accumulation of adenosine was widespread among all tissues examined. ADA-deficient mice also exhibited severe pulmonary insufficiency, bone abnormalities, and kidney pathology.