A 4-year-old child has recurrent sinopulmonary infections, absent tonsils on examination, and profound lymphopenia affecting both T and B cells. Adenosine deaminase (ADA) enzyme activity is undetectable. The toxic metabolite responsible for lymphocyte death in ADA-SCID is:
- A deoxyadenosine triphosphate (dATP) accumulating and inhibiting ribonucleotide reductase, arresting DNA synthesis ✓
- B Adenosine triphosphate accumulating in mitochondria
- C Inosine accumulated from adenosine deamination reaching toxic concentrations
- D Adenosine activating A2A receptors causing regulatory T-cell excess
Explanation
ADA catalyses the deamination of adenosine and deoxyadenosine to inosine and deoxyinosine respectively. In ADA deficiency, deoxyadenosine accumulates and is phosphorylated to dATP by deoxynucleoside kinases. Lymphocytes (especially T cells) have high deoxykinase activity and accumulate dATP to very high concentrations. dATP directly inhibits ribonucleotide reductase (the enzyme that converts ribonucleotides to deoxyribonucleotides) through allosteric feedback, depleting the dNTP pool needed for DNA replication and repair, triggering apoptosis. S-adenosylhomocysteine hydrolase is also inhibited, impairing methylation. ATP and inosine are not the primary culprits.
Reference: Harper's Illustrated Biochemistry, 32nd ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.