A 32-year-old woman with recurrent Neisseria meningitidis infections is found to have a deficiency in the terminal complement components. Which is the most common terminal complement component deficiency predisposing to meningococcal disease?

Explanation

## Terminal Complement Deficiency and Meningococcal Disease **Key Point:** C6 deficiency is the most commonly reported terminal complement component deficiency associated with recurrent *Neisseria meningitidis* infections in the published literature. ### Pathophysiology of Terminal Complement Deficiency The terminal complement components (C5–C9) form the membrane attack complex (MAC), which is essential for bactericidal killing of Gram-negative encapsulated organisms, particularly *Neisseria meningitidis*. 1. C5b initiates MAC assembly 2. C6 binds C5b to form the stable C5b-6 complex 3. C7, C8, and C9 are sequentially recruited → pore formation → bacterial lysis **High-Yield:** Deficiency of ANY terminal complement component (C5–C9) increases meningococcal disease risk 200–10,000-fold. Among these, **C6 deficiency is the most frequently reported** in epidemiological studies of complement-deficient patients with recurrent meningococcal disease (Figueroa & Densen, *Clin Infect Dis* 1991; Walport, *NEJM* 2001). ### Comparative Epidemiology of Terminal Complement Deficiencies | Component | Relative Frequency | Clinical Association | |-----------|-------------------|----------------------| | **C6** | **Most common** | Recurrent meningitis, bacteremia | | C7 | Second most common | Meningitis, gonococcemia | | C8 | Less common | Meningitis, bacteremia | | C5 | Less common | Severe meningitis, bacteremia | | C9 | Rare (mild phenotype) | Often asymptomatic or mild | **Clinical Pearl:** Patients with terminal complement deficiency typically present with: - Recurrent or unusual *Neisseria* species infections (*N. meningitidis*, *N. gonorrhoeae*) - Disseminated meningococcemia, often with less fulminant course than immunocompetent patients - Infections often occurring **later in life** (after maternal antibodies wane) - Relatively preserved immunity to other organisms ### Why C6 Deficiency is Most Common 1. **Epidemiological data:** Multiple case series and registry studies (including South African and European cohorts) consistently identify C6 deficiency as the most prevalent terminal complement deficiency among patients with recurrent meningococcal disease. 2. **Structural role:** C6 is the first component recruited after C5b cleavage; its absence completely abrogates MAC formation. 3. **Geographic variation:** C6 deficiency is particularly prevalent in South African Black and Sephardic Jewish populations, contributing to its overall higher reported frequency. **Mnemonic:** **C6 = "Complement 6 = Common culprit"** — Among the MAC components, C6 deficiency is the most common reason a patient cannot kill *Neisseria* efficiently. ### Clinical Management - **Diagnosis:** CH50 (total hemolytic complement) is low or absent; specific component assay confirms C6 deficiency - **Prevention:** Meningococcal vaccination (quadrivalent + serogroup B) — recommended even though efficacy is reduced without intact complement - **Prophylaxis:** Long-term prophylactic penicillin or ciprofloxacin considered in recurrent cases - **Monitoring:** Counsel patients on early recognition of meningitis symptoms and prompt medical attention *Reference: Walport MJ. Complement (two parts). N Engl J Med 2001;344:1058–1066; Figueroa JE, Densen P. Infectious diseases associated with complement deficiencies. Clin Microbiol Rev 1991;4:359–395.*