The Genetic and Metabolic Basis of ADA Deficiency

It is nearly 20 years since the first report of adenosine deaminase (ADA) deficiency occurring with severe combined immunodeficiency disease (SCID) [1]. At the time, research on purine metabolism in human disease was focused on questions related to gout. Investigation of the Lesch-Nyhan syndrome and phosphoribosylpyrophosphate (PPRP) synthetase overactivity fit this paradigm well, providing insight into mechanisms responsible for causing purine overproduction and hyperuricemia. The discovery of an association between ADA deficiency and SCID was entirely unexpected and identified an apparently important, but enigmatic, role of purine nucleoside metabolism in the development and function of the immune system. It also highlighted a lack of understanding of the biochemical control of the immune system at a time when the existence and functions of distinct lymphocyte subsets were only beginning to be appreciated. Giblett’s report [1] and her subsequent discovery of purinenucleoside phosphorylase (PNP) deficiency with selective T cell dysfunction offered a novel and challenging direction for future research.