Adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) catalyze sequential steps in the metabolism of purine ribo- and deoxyribonucleosides. They are expressed at very high levels in lymphoid cells. In patients with heritable deficiency of ADA or PNP, actions of their substrates or related metabolites impair lymphocyte differentiation, viability, and function, resulting in lymphopenia and immunodeficiency. Most patients with ADA deficiency lack both cell-mediated (T cell) and humoral (B cell) immunity, resulting in severe combined immunodeficiency disease (SCID). PNP-deficient children have defective cell-mediated immunity but may have normal, hyperactive, or reduced humoral immunity. Most patients with these disorders are severely affected and present during infancy and early childhood with recurrent infections involving pathogens and opportunistic organisms. Autoimmunity and neurologic abnormalities may occur with either enzyme deficiency, and hepatic dysfunction occurs in some patients with ADA deficiency.

ADA deficiency (MIM 102700) has been identified in several hundred families, and PNP deficiency in less than 50. Increasingly, enzyme-deficient patients with later onset and milder or atypical clinical presentations are being recognized. These diagnoses should be considered in patients with unexplained T-cell lymphopenia and late manifestations of immunodeficiency, such as chronic pulmonary insufficiency, sometimes with a history of autoimmunity and neurologic abnormalities, during the first two decades of life and even later. Diagnosis is made by finding absent or very low enzyme activity in erythrocytes or in nucleated blood cells. Heterozygotes have normal immune function and approximately half the normal erythrocyte enzyme levels. Prenatal diagnosis can be established by measuring enzyme activity in amniotic cells or chorionic villi.

Both conditions are inherited in an autosomal-recessive manner. Structural genes are located on chromosomes 20q13.11 (ADA) and 14q13 (PNP). Over 60 ADA gene mutations have been identified in immune-deficient patients. Several others have been found in a small group of individuals with so-called partial ADA deficiency, who are clinically unaffected owing to significant ADA activity in nucleated cells despite nearly absent levels in erythrocytes. There is a good correlation between the ADA activity expressed in vitro by mutant ADA alleles and clinical severity. Fourteen PNP mutations have been identified. The developmental and tissue-specific expression of ADA and PNP genes have been investigated, and the three-dimensional crystal structures of murine ADA and human PNP have been determined.

In ADA deficiency, levels of adenosine (Ado) and 2′-deoxyadenosine (dAdo) are elevated in the plasma; dAdo is elevated in the urine. Two major metabolic findings in erythrocytes are markedly elevated deoxyadenosine triphosphate (dATP) and reduced activity of S-adenosylhomocysteine (AdoHcy) hydrolase (usually <5 percent of normal), owing to suicide-like inactivation by dAdo; erythrocyte adenosine triphosphate (ATP) is decreased substantially in patients with SCID. The level of dATP in erythrocytes correlates with clinical severity and with the level of ADA activity expressed in Escherichia coli by mutant ADA alleles. In PNP deficency, plasma and urinary levels of PNP substrates are elevated, whereas uric acid is markedly decreased. In erythrocytes deoxyguanosine triphosphate (dGTP) may be detectable and guanosine triphosphate (GTP) may be decreased.

The primary lymphotoxic substrates of ADA and PNP—dAdo and 2′-deoxyguanosine (dGuo), respectively—are derived largely from the breakdown of DNA associated with cell death. Several effects of dAdo may contribute to lymphopenia and immune dysfunction in ADA deficiency: (a) dATP pool expansion can induce apoptosis in both dividing and nondividing lymphoid cells. This effect may be related to dATP-induced inhibition of ribonucleotide reductase, blocking DNA replication in dividing cells, and dATP-induced DNA strand breaks in nondividing lymphocytes. dATP directly activates a protease (caspase 9) involved in apoptosis. (b) AdoHcy accumulation can block vital S-adenosylmethionine (AdoMet)-mediated transmethylation reactions. (c) Formation of dATP from dAdo activates adenosine monophosphate (AMP) deamination and inosine monophosphate (IMP) dephosphorylation, leading to depletion of cellular ATP. Impaired lymphocyte function also may result from aberrant signal transduction, mediated by Ado acting through G protein–associated receptors, or from altered costimulatory function of T cell–associated ADA complexing protein CD26/dipeptidyl peptidase IV. In PNP deficiency, dGTP accumulation can inhibit ribonucleotide reductase and DNA replication in thymocytes, and can induce apoptosis.

Bone marrow transplantation from a human leukocyte antigen (HLA)-identical donor is the preferred treatment and can result in complete or partial immune reconstitution. Transplantation of T cell–depleted marrow from an HLA-haploidentical donor also has been successful, but is associated with greater morbidity and mortality and is less effective in restoring humoral immune function. For patients with ADA deficiency, an alternative to haploidentical transplantation is replacement therapy by intramuscular injection (once or twice weekly) of bovine ADA modified by attachment of polyethylene glycol (PEG-ADA). The high plasma ADA activity achieved with PEG-ADA, by degrading circulating dAdo, reverses intracellular dATP pool expansion and AdoHcyase inactivation. Immune function improves in most cases, resulting in sustained clinical benefit. Antibody to bovine ADA often becomes detectable with restoration of humoral immunity, but no allergic reactions have occurred and efficacy has usually not been impaired. About a dozen PEG-ADA–treated patients have become subjects for ongoing gene therapy experiments involving ex vivo retrovirus-mediated transfer of ADA complementary DNA. Mature blood T cells, as well as CD34+ cells isolated from bone marrow and umbilical cord blood, have been targeted. The efficiency of transducing stem cells has been low, but persistence of vector in myeloid cells and in T-lymphocytes has been demonstrated in several patients. These patients have continued to receive PEG-ADA, making evaluation of the benefit from gene transfer problematic.