A 3-year-old boy presents with severe combined immunodeficiency (SCID), recurrent infections, and absent B and T lymphocytes. Enzyme assay reveals near-absent adenosine deaminase (ADA) activity. Which toxic metabolite accumulates and selectively destroys lymphocytes?

• A Deoxyadenosine — phosphorylated to dATP, which inhibits ribonucleotide reductase and induces lymphocyte apoptosis ✓
• B Hypoxanthine — inhibits ribonucleotide reductase
• C Adenosine — activates A2A receptors causing lymphocyte anergy
• D Inosine — forms xanthine and uric acid, causing renal toxicity

Explanation

ADA deficiency blocks conversion of adenosine and deoxyadenosine to inosine. Deoxyadenosine accumulates and is phosphorylated by deoxycytidine kinase (highly active in lymphocytes) to dATP; elevated dATP inhibits ribonucleotide reductase (blocking DNA synthesis), activates p53-mediated apoptosis, and inhibits S-adenosylhomocysteine hydrolase (raising SAH, impairing methylation). Lymphocytes (especially T cells) are particularly vulnerable due to high deoxycytidine kinase activity. ADA-SCID was the first disease treated by gene therapy.

Reference: Harper's Illustrated Biochemistry, 32nd ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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