Introduction 
1 .0 
1.1 Severe Combined Immunodeficiency (SCID) 
SCID is a group of inherited immunodeficiency disorders characterized by profound cellular and 
humoral immune dysfunction resulting in recurrent opportunistic infections and failure to 
thrive with onset in the first few months of life (1). Those affected usually die within the first 
years of childhood unless successful immunologic reconstitution is achieved by transplantation. 
In 20-25% of SCID cases, a unique autosomal recessive form of the disorder can be identified 
which results in deficiency of the purine catabolic enzyme adenosine deaminase [ADA, EC 
S.5.4.4] (2). ADA deaminates adenosine to inosine and deoxyadenosine (dAdo) to deoxyinosine 
(Appendix 13.1, Figure 1). In the absence of ADA, dAdo accumulates in the tissues and may 
be phosphorylated to form deoxyATP with accumulation of high intracellular levels of both (3- 
5). 
The mechanisms through which these biochemical abnormalities result in combined 
immunodeficiency remain incompletely understood. The bulk of the evidence suggests that the 
intracellular accumulation of dAdo and its metabolites, particularly deoxyATP, results in 
inhibition of DNA synthesis and cell death(6-8). T-lymphocytes are preferentially affected in 
this disorder because they express higher concentrations of the kinases which phosphorylate 
deoxyadenosine to dATP than other tissues, resulting in T-lymphopenia and profound cellular 
immunodeficiency. 
ADA deficiency with severe combined immunodeficiency is a genetically heterogeneous disorder 
with a variety of mutations having been identified in the ADA protein that are responsible for 
alterations in ADA activity and enzyme stability and survival (9-13). A spectrum of partial 
ADA enzyme deficiencies has been identified in a number of kindreds. These individuals have 
deficient erythrocyte ADA activity, 5-20% of normal ADA activity in their peripheral 
lymphocytes and are in general clinically healthy. 
1 .2 Bone Marrow Transplantation for the Correction of ADA Deficient Severe 
Combined Immunodeficiency 
Bone marrow transplantation with HLA-matched marrow has been curative for ADA normal 
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