ADA

Abstract

Adenosine deaminase (ADA) plays a significant role in purine nucleoside metabolism. It plays a more critical role in murine than human fetal development. ADA deficiency in humans results in severe combined immunodeficiency disease (SCID), characterized by the virtual absence of both T and B lymphocytes. This chapter presents a study in which ADA-deficient mice completed prenatal development and were born at the expected time and frequency, they were either stillborn or succumbed within the first three days after birth. Histological examination showed severe liver cell degeneration, incomplete expansion of the lungs, and the death of small intestinal cells. In humans, ADA deficiency was associated with impaired T-cell development. In mice, however, all ADA-deficient animals that died within the first postnatal day showed a histologically normal thymus without signs of immunodeficiency or infectious disease. The purine salvage pathway of ADA-deficient mice was metabolically deranged. The ADA substrates, adenosine (Ado) and deoxyadenosine (dAdo), were increased. However, adenine deoxyribonucleotides (dAXP) in thymuses of ADA-deficient mice were only modestly elevated, which may explain the thymic sparing. The analysis of the metabolic effects of the absence of ADA on the transmethylation pathway showed that 5-adenosylhomocysteine hydrolase activity was reduced more than 85%, indicating significant exposure to dAdo during fetal development. The absence of ADA in mice results in severe liver cell damage but an apparently normal thymus. Although liver involvement in ADA-deficient mice is more severe than in humans, elevated serum transaminase levels of uncertain etiology are common in ADA-deficient severe combined immunodeficiency disease patients and may indicate subclinical liver damage.