2 NEWLY IDENTIFIED MUTATIONS (THR233ILE AND LEU152MET) IN PARTIALLY ADENOSINE DEAMINASE-DEFICIENT (ADA(-)) INDIVIDUALS THAT RESULT IN DIFFERING BIOCHEMICAL AND METABOLIC PHENOTYPES

Deficiency of adenosine deaminase (ADA(-)) results in autosomal recess ive immunodeficiency disease of varying severity. Partial ADA(-) [ADA deficiency in erythrocytes (RBCs) but substantial ADA in non-RBCs] has also been identified, primarily by population screening of healthy ad ults In Africa and newborns in New York State. Normal immune function and/or minimal elevations of toxic metabolites in childhood suggested that partial ADA deficiency was benign and therefore that six mutation s identified in partially ADA-deficient newborns and expressing 8-80% of normal ADA in non-RBCs were not pathogenic. However, the lowest act ivity mutation (Arg211Cys) has now been reported in patients with adul t-onset immunodeficiency. We have now molecularly and biochemically st udied two additional individuals whom we found to represent opposite e nds of the spectrum of partial ADA deficiency as to biochemical abnorm alities and age of ascertainment. Homozygosity for a newly identified Leu152Met mutation expressing considerably less activity than the path ogenic Arg211Cys mutation was found in a currently healthy 10-year-old Afghanistani child (ascertained at birth). He had the highest accumul ation of the metabolite dATP among 13 partially ADA-deficient patients studied, but considerably lower than in those with immunodeficiency. Homozygosity for a newly identified Thr233Ile mutation expressing some what greater ADA activity than Arg211Cys was found in a healthy young adult Kung individual, associated with very low metabolite concentrati ons. Biochemical findings and a family history suggestive of immunodef iciency in prior offspring support the idea that the Leu152Met mutatio n could result in disease in homozygous individuals challenged by seve re environmental insult or in heterozygosity with a null mutation. The pathogenicity of the Thr233Ile mutation, as well as a previously desc ribed Ala215Thr mutation with relatively lower activity is less likely but will only be determined by long-term observation of individuals c arrying these mutations. Although, in contrast to other partial mutati ons, neither of these two mutations are at CpG hot spots, the frequenc y of CpG mutations remains high for partial mutations but is also simi larly high in ADA(-) immunodeficient patients (5/8 vs 12/21).