Immunodeficiency Due to Defects of Purine Metabolism

Abstract Genetic deficiency of the purine salvage enzyme adenosine deaminase (ADA) provides the molecular basis for approximately 40% of autosomal recessive cases of severe combined immunodeficiency (SCID) and therefore approximately 20% of all cases of SCID (Hirschhorn, 1979b; Bertrand et al., 1999; Buckley, 2000). The identification, over two decades ago, of deficiency of ADA as the basis for immunodeficiency (MIM #102700) was serendipitous and unexpected (Giblett et al., 1972). By contrast, immunodeficiency due to genetic deficiency of purine nucleoside phosphorylase (PNP), the next enzyme in the purine salvage pathway, was identified by specific screening for deficiency of enzymes in this pathway in immunodeficient patients (Giblett et al., 1975). PNP immunodeficiency (MIM + 164050) is even rarer than ADA deficiency, having been reported in fewer than 30 unrelated families (Markert, 1991; Carpenter et al., 1996; Markert et al., 1997; Sasaki et al., 1998; Dalal et al., 2001; Baguette et al., 2002; Moallem et al., 2002; Tsuda et al., 2002; Tabarki et al., 2003; Grunebaum et al., 2004). Study of patients with these two disorders has shed light on the significance of the purine salvage pathway for lymphoid cells as well as on the potential for development of new antileukemic agents (Hirschhorn, 1993; Markert, 1994; Suetsugu et al., 1999; Hershfield and Mitchell, 2001; Dillman, 2004).