![]() concluded the following: “Since ADA anenzymia and the inherited diseases of cellular immunity are extremely rare, their coexistence in two unrelated patients seems very unlikely to be fortuitous.” Alternatively, it was speculated that they might have a short chromosomal deletion encompassing the ADA gene and a nearby critical immune response gene. Giblett and colleagues proposed that the two patients might have rare mutant alleles for the ADA gene. Mutations in the HPRT gene were known to cause the neurologic disorder Lesch-Nyhan syndrome and its associated gouty arthritis ( 2), but this pathway was not thought to be important for the immune system. These were completely unexpected findings, as no precedent existed for ADA deficiency in humans or for ADA's role in either the development or the function of the immune system.ĪDA is part of the purine salvage pathway that includes the enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Subsequently, a second patient with severe cellular immunodeficiency was studied and also found to be ADA deficient. Much to her surprise, starch gel electrophoresis indicated that the RBCs of the patient were completely devoid of ADA enzyme activity! The parents showed detectable, but reduced, ADA activity, suggesting an autosomal recessive mode of inheritance. It was hoped that she could shed light on the relationships among the family members of the patient by examining isozyme patterns for the enzyme ADA. Giblett at the King County Central Blood Bank. Thus, the patient's physicians sent blood samples to Dr. In the case of one of two patients described by Giblett et al., routine HLA typing of family members failed to identify suitable donors. ![]() In those days, the only “cure” for severe immunodeficiency diseases was bone marrow transplantation (BMT) from a histocompatible donor. However, the gene defects responsible for these devastating disorders were unknown. In the early 1970s, several primary immunodeficiency diseases, including SCID, X-linked agammaglobulinemia, and Wiskott-Aldrich syndrome, were well known to pediatric immunologists and presumed to be caused by single gene defects based on patterns of inheritance. This finding led to the eventual development of novel therapies not only for ADA deficiency but also for other immunodeficiency disorders and certain leukemias. Eloise Giblett and colleagues ( 1) ushered in a new era in the investigation of the molecular mechanisms underlying primary immunodeficiency disorders. The serendipitous discovery of adenosine deaminase (ADA) deficiency in two patients with cellular immunodeficiency in 1972 by Dr.
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