In X-linked agammaglobulinemia (Bruton's disease), the molecular defect is absence of functional BTK (Bruton's tyrosine kinase), which blocks B-cell development at the:
- A Transition from naive to activated B cell
- B Germinal center reaction (impaired somatic hypermutation)
- C Pro-B to pre-B cell transition (failure of pre-BCR signaling) ✓
- D Pre-B to immature B cell transition (failure of light-chain rearrangement)
Explanation
BTK is required for downstream signaling of the pre-B cell receptor (pre-BCR), which forms transiently during heavy-chain (μ) rearrangement. Without BTK signaling, the survival and proliferative signal from pre-BCR is absent, arresting differentiation at the pro-B → pre-B transition and resulting in absent mature B cells and absent immunoglobulins of all classes. T cells are unaffected. Patients suffer recurrent bacterial infections after 6 months (when maternal IgG wanes). Germinal center defects (e.g., CD40L deficiency) cause hyper-IgM syndrome, not agammaglobulinemia. Light-chain rearrangement occurs after the pre-BCR checkpoint.
Reference: Robbins & Cotran Pathologic Basis of Disease, 10th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.