## Adenosine Deaminase (ADA) Deficiency ### Enzyme & Pathway **Key Point:** ADA catalyzes the deamination of adenosine to inosine and deoxyadenosine to deoxyinosine in the purine salvage pathway. ### Mechanism of Lymphocyte Toxicity 1. ADA deficiency → deoxyadenosine accumulates 2. Deoxyadenosine is phosphorylated → deoxyadenosine monophosphate (dAMP) → deoxyadenosine triphosphate (dATP) 3. **dATP accumulates to toxic levels** in lymphocytes (which have high deoxycytidine kinase activity) 4. Elevated dATP inhibits ribonucleotide reductase → blocks deoxyribonucleotide synthesis 5. Impaired DNA synthesis → lymphocyte apoptosis and death ### Why Lymphocytes Are Selectively Affected **Clinical Pearl:** Lymphocytes are uniquely vulnerable because they: - Have the highest metabolic rate during proliferation - Express high levels of deoxycytidine kinase (phosphorylates deoxyadenosine) - Depend critically on deoxyribonucleotide synthesis for DNA replication ### Clinical Features - Autosomal recessive SCID (Severe Combined Immunodeficiency) - Accounts for ~10–15% of all SCID cases - Presents with recurrent infections, failure to thrive, opportunistic infections (PCP, CMV, candidiasis) - Can present as adenosine deaminase deficiency with extra-lymphoid manifestations (neurologic, skeletal abnormalities) **High-Yield:** ADA-SCID is one of the few primary immunodeficiencies with significant non-immune organ involvement due to adenosine toxicity in the brain and bone.
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