A 6-month-old male infant has severe recurrent infections with gram-negative and gram-positive organisms, fungi, and opportunistic pathogens. He has profound lymphopenia with absence of T cells, B cells, and NK cells. Adenosine deaminase (ADA) activity is markedly reduced. The cytotoxic metabolite accumulating in ADA deficiency that is particularly toxic to lymphocytes is:

• A Adenosine monophosphate (AMP)
• B S-adenosylhomocysteine
• C Deoxyadenosine triphosphate (dATP) ✓
• D Deoxyinosine

Explanation

ADA deficiency causes SCID due to accumulation of deoxyadenosine and its phosphorylated metabolite deoxyadenosine triphosphate (dATP). Lymphocytes express high levels of deoxynucleoside kinases and low levels of 5'-nucleotidase, causing preferential accumulation of dATP in lymphocytes compared to other cell types. Elevated dATP inhibits ribonucleotide reductase (halting DNA synthesis), promotes apoptosis via caspase activation, and also inhibits S-adenosylhomocysteine hydrolase, leading to S-adenosylhomocysteine accumulation and impaired methylation reactions. Deoxyinosine accumulates in purine nucleoside phosphorylase (PNP) deficiency.

Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.