A 4-year-old child with recurrent infections has profound lymphopenia affecting both T and B cells. Newborn screening showed elevated deoxyadenosine. The enzyme deficiency responsible and the mechanism of lymphocyte death is:

• A Adenosine deaminase (ADA) deficiency; dATP accumulation inhibiting ribonucleotide reductase and inducing apoptosis ✓
• B Purine nucleoside phosphorylase (PNP) deficiency; dGTP accumulation inhibiting ribonucleotide reductase
• C HGPRT deficiency; dIMP accumulation causing lymphocyte mitochondrial dysfunction
• D 5'-nucleotidase deficiency; dCTP imbalance triggering lymphocyte apoptosis via p53

Explanation

ADA deficiency causes accumulation of deoxyadenosine, which is phosphorylated to dATP in lymphocytes (particularly T cells which have high deoxynucleoside kinase activity). Elevated dATP allosterically inhibits ribonucleotide reductase (by binding the activity site), blocking DNA synthesis, and also activates DNA-damage checkpoint-mediated apoptosis. B cell loss is secondary to T cell loss plus direct effects. ADA deficiency is the most common cause of autosomal recessive SCID and was the first target of gene therapy.

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

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.