Severe Combined Immunodeficiency (SCID) describes a range of clinically and genetically diverse immune system disorders, characterized by compromised T-Cell development, and further classification is based on the presence or absence of B lymphocytes and natural killer (NK) cells. SCID due to Adenosine Deaminase (ADA) deficiency is the second most common SCID disorder, representing 15% of all SCID cases, with an incidence ranging between 1:200,000 and 1:1,000,000 births. Low or aberrant ADA enzyme activity in developing white blood cells leads to dysfunctional T-cell, B-cell, and NK cell, resulting in compromised humoral and cellular immunity. The weakened immune system becomes particularly vulnerable to opportunistic organisms, consequently, prominent clinical symptoms involve various recurring infections- including pneumonia, meningitis, and sepsis, as well as chronic skin infections, yeast infections, and gastrointestinal infections. Cases usually exhibit an abnormally small thymus due to the effect of ADA deficiency on developing T-cells. Spleen abnormalities, a lack of tonsils and lymph nodes, thrombocytopenia, as well as skeletal and neurological abnormalities, are among the clinical features of ADA deficiency.
Severe lymphopenia is the diagnostic hallmark of all SCID disorders, and is detected through complete blood count and flow cytometry analysis of white blood cell subsets. Early diagnosis of ADA-SCID involves prenatal testing of ADA enzyme activity through chorionic villus sampling or amniocentesis, as well as assessing enzyme levels in fetal blood samples. ADA-SCID can present in infancy and is fatal within one year if left untreated. Non-curative treatment of ADA-SCID involves enzyme replacement therapy (ERT). ERT can temporarily ameliorate infections; however restoring immune system function requires bone marrow transplantation (BMT) or gene therapy (GT). BMT performed during the first three months of infancy have a high success rate, offering post-transplantation survival that can extend to several years. GT studies are currently ongoing, and involve the transduction of host hematopoietic stem cells with the wild type ADA gene using retroviral vectors.
ADA-SCID is an autosomal recessive condition originating from mutations in the Adenosine Deaminase (ADA) gene. The Adenosine deaminase enzyme functions in the purine metabolism and salvage pathways, specifically catalyzing the deamination of adenosine and deoxyadenosine. Due to the high mitotic and apoptotic activity of lymphocytes undergoing development and selection, ADA is essential for the metabolic maintenance of the immune system. Loss of ADA function leads to the abnormal buildup of deoxyadenosine, and consequently dATP buildup, which is cytotoxic to developing lymphocytes. Adenosine toxicity has been shown to interfere with mature T-cell receptor signaling and activation. Absent ADA activity leads to early-onset ADA-SCID, whereas cases retaining some immune function can present after a delay from childhood to adulthood.