Foundations · Year 1 · from Foundations
Case 1: Diphtheria (EF-2 Inhibition)
Clinical Image
Source: Wikipedia - Diphtheria - CC BY-SA 3.0
Case Presentation
A 4-year-old unvaccinated child from an underserved community presents with fever, sore throat, and difficulty breathing for 3 days. He has not received routine childhood vaccinations. Physical examination reveals cervical lymphadenopathy ("bull neck"), low-grade fever, and an adherent grayish-white pseudomembrane covering his tonsils and pharynx that bleeds when an attempt is made to remove it. He also has a hoarse voice suggesting laryngeal involvement. Nasopharyngeal culture grows Corynebacterium diphtheriae. He is immediately treated with diphtheria antitoxin (to neutralize circulating toxin) and antibiotics (erythromycin). The mechanism of diphtheria toxin is explained: it is an AB toxin where the B subunit binds heparin-binding EGF-like growth factor receptor, enabling entry into cells. The A subunit catalyzes ADP-ribosylation of elongation factor 2 (EF-2), specifically modifying a unique amino acid called diphthamide. This irreversibly inactivates EF-2, blocking translocation during protein synthesis and halting all protein production in the cell. Each toxin molecule can inactivate many EF-2 molecules catalytically, making the toxin extraordinarily potent. Heart block develops on day 5 (myocarditis from toxin effect), requiring temporary pacing. He survives but requires long-term cardiac monitoring.
Key Learning Points
- Diphtheria toxin ADP-ribosylates elongation factor 2 (EF-2), inactivating it and blocking the translocation step of protein synthesis; this affects all cells but is particularly devastating to high-metabolic tissues like heart and nerve
- EF-2 is essential for translocation, the step that moves the ribosome one codon along the mRNA after peptide bond formation; without functional EF-2, protein synthesis halts completely
- The modification is at diphthamide, a unique post-translationally modified histidine residue found only in EF-2, explaining the toxin's specificity; antitoxin must be given early before toxin enters cells