Partial adenosine deaminase deficiency: another family from southern Africa

Human Genetics (Impact Factor: 4.82). 12/1986; 74(3):307-12. DOI: 10.1007/BF00282554
Source: PubMed


Adenosine deaminase (ADA) from a partially ADA-deficient Xhosa man has been characterized. This is only the second such case described in southern Africa, the previous one being a Kalahari San ("Bushman"). Red blood cell ADA levels were found to be only 6-9% of normal whereas his white cell ADA levels were much higher at 30% of normal. The stability of the enzyme at 57 degrees C was shown to be greatly decreased indicating a mutation resulting in an enzyme with decreased stability in vivo. The Michaelis constant (Km) for adenosine was found to be normal. Deoxy-ATP levels in the red cells were elevated 2- to 3-times above normal, although this appears to be of no immunological consequence. Starch gel electrophoresis of red cell ADA from family members of the index case, in conjunction with red cell ADA activity levels, suggested that both parents carried a gene for partial ADA deficiency. Isoelectric focusing studies suggested that the two parental partial ADA-deficiency genes were not the same. Electrophoretic studies also revealed that another rare allele of ADA, possibly ADA*5, was segregating within the same family although this event appears to be unconnected with the ADA partial deficiency. A Xhosa population sample was assayed for red cell ADA activity. The results suggested a frequency of 0.015 +/- 0.010 for ADA partial-deficiency alleles, although the number of different alleles involved is not known.

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    ABSTRACT: Deficiency of adenosine deaminase (ADA-) results in autosomal recessive 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 adults 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 mutations identified in partially ADA-deficient newborns and expressing 8-80% of normal ADA in non-RBCs were not pathogenic. However, the lowest activity mutation (Arg211Cys) has now been reported in patients with adult-onset immunodeficiency. We have now molecularly and biochemically studied two additional individuals whom we found to represent opposite ends of the spectrum of partial ADA deficiency as to biochemical abnormalities and age of ascertainment. Homozygosity for a newly identified Leu152Met mutation expressing considerably less activity than the pathogenic Arg211Cys mutation was found in a currently healthy 10-year-old Afghanistani child (ascertained at birth). He had the highest accumulation 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 somewhat greater ADA activity than Arg211Cys was found in a healthy young adult Kung individual, associated with very low metabolite concentrations. Biochemical findings and a family history suggestive of immunodeficiency in prior offspring support the idea that the Leu152Met mutation could result in disease in homozygous individuals challenged by severe environmental insult or in heterozygosity with a null mutation. The pathogenicity of the Thr233Ile mutation, as well as a previously described Ala215Thr mutation with relatively lower activity is less likely but will only be determined by long-term observation of individuals carrying these mutations. Although, in contrast to other partial mutations, neither of these two mutations are at CpG hot spots, the frequency of CpG mutations remains high for partial mutations but is also similarly high in ADA- immunodeficient patients (5/8 vs 12/21).
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    ABSTRACT: Severe combined immunodeficiency due to adenosine-deaminase defect (ADA-SCID) is usually deadly in childhood because of severe recurrent infections. When clinical diagnosis is done, permanent damages due to infections or metabolite accumulation are often present. Gene therapy, bone marrow transplantation or enzyme replacement therapy may be effective if started early. The aim of this study was to set-up a robust method suitable for screening with a minimized preparation process and with inexpensive running costs, for diagnosing ADA-SCID by tandem mass spectrometry. ADA-SCID satisfies all the criteria for inclusion in a newborn screening program. We describe a protocol revised to incorporate adenosine and 2-deoxyadenosine testing into an expanded newborn screening program. We assessed the effectiveness of this approach testing dried blood spots from 4 genetically confirmed early-onset and 5 delayed-onset ADA-SCID patients. Reference values were established on 50,000 healthy newborns (deoxyadenosine <0.09μmol/L, adenosine <1.61μmol/L). We also developed a second tier test to distinguish true positives from false positives and improve the positive predictive value of an initial abnormal result. In the first 18 months, the pilot project has identified a newborn with a genetically confirmed defect in adenosine deaminase (ADA) gene. The results show that the method having great simplicity, low cost and low process preparations can be fully applicable to a mass screening program.
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