Abstract
ABSTRACT.: Approximately 20 years ago, Giblett and coworkers serendipitously discovered that in some patients with the syndrome of severe combined immunodeficiency, the disease is due to an inherited deficiency of the enzyme adenosine deaminase (ADA). This then led to the discovery that inherited deficiency of the next enzyme in the same pathway for purine salvage, purine nucleoside phosphorylase, results in a profound defect in cell-mediated immunity. These two disorders, sometimes termed “purinergic immunodeficiency disorders,” were the first of the inherited immunodeficiency disorders in which the specific molecular basis was determined. Although both are rare diseases, they are of importance for several reasons. First, they are among the few inherited disorders of which some children can be cured by a single treatment; second, they are ideally suited for gene therapy; and third, the pathologic mechanisms can tell us more about the nature of the immune system and have already allowed development of chemotherapy for some malignancies of the immune system. Knowledge of the specific defects has also facilitated diagnosis, counseling of families, and development of new approaches to therapy. This article focuses on ADA deficiency, briefly reviews the clinical and biochemical findings to provide a background for the next two articles in this supplement issue, and details work in progress with respect to several aspects of the specific molecular defects in different patients. Some of the generalizations that are beginning to emerge from studies of other disease loci as to the nature, diversity, and distribution of mutations at different genetic loci and the emerging correlations of phenotype with genotype are reviewed to provide a framework for examining the molecular defects in ADA deficiency. The status of our knowledge of the ADA locus with respect to analysis of mutations and possible correlations with genotype is then considered. It is important to note that although the ADA gene has been isolated and the gene product is known there are still unanswered questions.
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Hirschhorn, R. Overview of Biochemical Abnormalities and Molecular Genetics of Adenosine Deaminase Deficiency. Pediatr Res 33 (Suppl 1), S35–S41 (1993). https://doi.org/10.1203/00006450-199333011-00008
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DOI: https://doi.org/10.1203/00006450-199333011-00008
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