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The degree of immunodeficiency associated with deficiency of adenosine deaminase (ADA) is variable. Most patients are infants with severe combined immunodeficiency (SCID), but in about 20 percent immune dysfunction becomes manifest later in childhood ("delayed-onset"); several patients with "late" or "adult" onset of immune dysfunction have been diagnosed at 15-39 years. Over 40 ADA gene mutations have thus far been identified. To better define the genotype-phenotype relationship, we report 7 novel ADA mutations, including 5 missense mutations (G74C, V129M, G140E, R149W, Q199P) and two short deletions (462delG, E337del). These were identified among 7 patients (3 with SCID and 4 with delayed-onset). A homozygote for 462delG had SCID, whereas patients homozygous or heterozyous for V129M had delayed-onset. Two other delayed-onset patients, one heterozygous for G74C and the other for Q199P, each had a second allele carrying the previously reported "severe" mutation G216R. These findings are consistent with previous observations suggesting that, in general, SCID occurs when both alleles eliminate ADA function, and a milder phenotype when at least one allele can supply a low level of function.

PEG-ADA is a long-circulating form of adenosine deaminase (ADA) that has been in use for > 8 years as replacement therapy for severe combined immunodeficiency disease due to ADA deficiency. Treatment with PEG-ADA almost completely corrects metabolic abnormalities, allowing the recovery of a variable degree of immune function. Although not normal, the level of function achieved has in most cases been sufficient to protect against opportunistic and life-threatening infections. PEG-ADA has been used as an alternative for patients who lack an HLA-identical bone marrow donor, but are judged to be at too high a risk for undergoing HLA-haploidentical marrow transplantation. To date, mortality and morbidity with PEG-ADA have been less than for the latter procedure. PEG-ADA has also been an important adjunct to attempts to develop somatic cell gene therapy for ADA deficiency, although its continued use poses a problem for evaluation of the benefit of gene therapy. As a true "orphan drug" developed to treat a very small patient population, the cost per patient of PEG-ADA is very high.