A male infant with recurrent bacterial and fungal infections has absent T cells, absent B cells, and absent NK cells on flow cytometry. Enzyme assay shows absent adenosine deaminase (ADA) activity. The pathophysiology involves accumulation of which toxic metabolite in lymphoid progenitors?

• A Hypoxanthine accumulation causing purine synthesis suppression
• B Deoxyadenosine and dATP, which inhibit ribonucleotide reductase and induce lymphoid progenitor apoptosis ✓
• C Adenosine accumulation activating A2A receptors causing T-cell anergy
• D Uric acid deposition causing lymphoid necrosis

Explanation

ADA deficiency causes SCID through accumulation of deoxyadenosine, which is phosphorylated to dATP in lymphoid cells (which lack efficient nucleoside phosphorylase). Elevated dATP allosterically inhibits ribonucleotide reductase, blocking DNA synthesis, and also induces apoptosis of lymphoid progenitors via activation of apoptotic pathways. This preferentially affects lymphoid cells because they have high levels of deoxynucleoside kinases. All lymphoid lineages (T, B, NK) are affected, producing T−B−NK− SCID — the most common cause of autosomal recessive SCID.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

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