| Phenotype / Clinical Feature | HPO term suggestion | Frequency in affected individuals (with citation) | Age of onset | Severity description | Key notes / mechanism |
|---|---|---|---|---|---|
| Recurrent invasive meningococcal disease (meningococcal sepsis and/or meningitis) | HP:0005381 Recurrent bacterial infections; HP:0002718 Recurrent invasive bacterial infection; HP:0002013 Meningitis; HP:0100806 Sepsis | In a UK multicenter cohort of terminal pathway deficiency, 48% had meningococcal and/or other deep-seated bacterial infection; 45% had meningococcal septicemia and 18% meningococcal meningitis; median number of meningococcal infections was 1 (range 0–5). Reviews note ~40–50% of individuals with MAC-component deficiency experience meningococcal infections, and terminal pathway deficiency confers a 7,000- to 10,000-fold higher risk of invasive meningococcal disease (pqac-00000004, pqac-00000007, pqac-00000003, pqac-00000006, pqac-00000008) | Usually childhood to adolescence; median age at first infection 9 years (range 1–25) in the UK cohort, but presentations can occur in adulthood (pqac-00000004, pqac-00000007, pqac-00000003) | Often severe but paradoxically may be less fulminant than properdin/factor D deficiency; 22% required ICU in the UK cohort; recurrence is common without recognition/prevention (pqac-00000004, pqac-00000007, pqac-00000002) | Caused by inability to form membrane attack complex (MAC; C5b-9), impairing serum bactericidal activity against Neisseria meningitidis. Less common serotypes can predominate: among typed UK infections, 43% were serogroup B and 43% serogroup Y, with occasional W and E (pqac-00000004, pqac-00000007, pqac-00000003, pqac-00000008) |
| Recurrent meningococcal meningitis | HP:0001287 Meningitis | In the UK cohort, 18% had meningococcal meningitis; case reports describe repeated episodes, including 3 episodes in a Qatari man with C7 deficiency over time (pqac-00000004, pqac-00000007, pqac-00000003) | Often school age, adolescence, or young adulthood; case reports include onset at ages 7, 18, and 20 years in one patient (pqac-00000003) | Potentially life-threatening but survivors can recover fully; repeated episodes markedly affect schooling, work, and psychosocial security due to fear of recurrence (inferred from recurrent severe infection burden) (pqac-00000003, pqac-00000004) | Reflects failed terminal complement-mediated killing in bloodstream/CSF. Patients may develop meningitis despite prior meningococcal vaccination if the underlying complement defect is unrecognized (pqac-00000003, pqac-00000009) |
| Meningococcal septicemia / fulminant meningococcemia | HP:0100806 Sepsis | 45% in the UK cohort had meningococcal septicemia; septic presentation was a major risk factor for ICU admission (relative risk 16.3 in the cohort analysis) (pqac-00000007) | Childhood through adulthood; median first infection age 9 years (pqac-00000007) | High acute severity; 22% of the full cohort required intensive care; can be fatal (pqac-00000004, pqac-00000007) | Caused by bloodstream proliferation of Neisseria when MAC-dependent killing fails. Petechial rash and shock may occur, as in reported C7-deficient children with meningococcal sepsis (pqac-00000003, pqac-00000009) |
| Chronic meningococcemia | HP:0002718 Recurrent invasive bacterial infection; HP:0001945 Fever; HP:0000988 Skin rash | Reported as a recognized phenotype of terminal complement deficiency in expert review/teaching materials, but no robust percentage available from the recent cohort literature reviewed here (pqac-00000002) | Variable; often later childhood to adulthood based on historical phenotype descriptions (pqac-00000002) | Typically subacute/relapsing rather than fulminant; may impair quality of life through prolonged fever, rash, arthralgia, and repeated healthcare visits (pqac-00000002) | Represents persistent or recurrent meningococcal bacteremia due to incomplete bacterial clearance in MAC deficiency (pqac-00000002, pqac-00000008) |
| Meningococcal arthritis / septic arthritis | HP:0001386 Arthritis; HP:0002758 Septic arthritis | 8% had meningococcal arthritis in the UK cohort (pqac-00000007) | Usually pediatric to young adult, often accompanying invasive infection (pqac-00000007) | Moderate to severe; joint pain and functional limitation can affect mobility and daily activities during episodes (pqac-00000007) | May occur as a focal complication of invasive meningococcal infection in terminal pathway deficiency (pqac-00000007) |
| Disseminated gonococcal infection | HP term not specific; suggest HP:0002718 Recurrent invasive bacterial infection | Recognized hallmark susceptibility in terminal complement deficiency; recent mechanistic review notes individuals lacking terminal complement have >300-fold increased susceptibility to local and disseminated Neisseria gonorrhoeae infection, but disease-specific cohort frequency in inherited deficiency is not well quantified in the retrieved sources (pqac-00000002, pqac-00000005) | Typically after sexual debut / adolescence or adulthood (pqac-00000002) | Can be severe and recurrent; may present with bacteremia, arthritis, dermatitis, and hospitalization; important counseling implication for adolescents/adults (pqac-00000002, pqac-00000005) | MAC is a major defense against pathogenic Neisseria species beyond N. meningitidis. Terminal complement failure impairs gonococcal killing and increases dissemination risk (pqac-00000005) |
| Non-meningococcal deep bacterial infections | HP:0002718 Recurrent invasive bacterial infection | 34% had non-meningococcal sepsis and related serious bacterial infections in the UK cohort, including respiratory infection, pyogenic meningitis, osteomyelitis/septic arthritis, and skin/soft tissue infection (pqac-00000007) | Variable, from infancy to adulthood (pqac-00000007) | Variable; can include serious invasive disease, though Neisseria susceptibility remains the dominant phenotype (pqac-00000004, pqac-00000007) | Terminal complement defects primarily impair killing of Neisseria, but some patients also develop other invasive bacterial infections, likely reflecting broader compromise in bactericidal activity against select encapsulated/Gram-negative organisms (pqac-00000001, pqac-00000007) |
| Asymptomatic carrier state / family-identified disease | No direct HPO disease-feature term; consider HP:0033704 Reduced complement activity | 52% of the UK cohort were asymptomatic and diagnosed because of family history; 80% had an affected family member (pqac-00000004, pqac-00000007) | Congenital/genetic, often detected only after a relative is diagnosed (pqac-00000004, pqac-00000007) | Clinically silent until first invasive infection; nevertheless high lifelong infection risk mandates prevention planning (pqac-00000004, pqac-00000007, pqac-00000016) | Important knowledge-base phenotype because absence of prior infection does not exclude severe risk. Family screening is therefore a major secondary-prevention strategy (pqac-00000004, pqac-00000007, pqac-00000016) |
| Laboratory phenotype: absent CH50 and AH50 (except some C9-deficient cases may show residual activity) | HP:0012378 Abnormal complement system physiology; HP:0033704 Reduced complement activity | Functional terminal pathway deficiency characteristically shows absent or markedly reduced classical and alternative pathway hemolytic activity; examples include C7-deficient case with classical 0.6%, lectin 0.2%, alternative 0.1% activity (pqac-00000006, pqac-00000009, pqac-00000002) | Congenital; detectable at any age once tested | Usually a stable constitutional laboratory abnormality outside periods of consumption from sepsis or inflammatory disease (pqac-00000002, pqac-00000006) | Core diagnostic phenotype caused by failure to assemble C5b-9; often accompanied by absent specific terminal component antigen/protein (e.g., absent C7 on Western blot) (pqac-00000006, pqac-00000009) |
| Autoimmune manifestations | HP:0002960 Autoimmunity | Much less prominent than in early classical pathway deficiencies; terminal pathway deficiency is described mainly as an infection phenotype. Reviews of complement deficiency note autoimmunity can occur across complement disorders broadly, but recent terminal-pathway cohorts emphasize invasive infection rather than autoimmune disease, and no strong frequency estimate was identified for C5-C9 deficiency specifically (pqac-00000001, pqac-00000006, pqac-00000013) | Variable / not well defined for terminal pathway deficiency | Usually not the dominant clinical problem in late complement deficiency (pqac-00000001, pqac-00000013) | Unlike C1/C2/C4 deficiency, C5-C9 deficiency chiefly disrupts MAC-mediated bacterial lysis, so mechanistic linkage is strongest for Neisseria susceptibility rather than immune-complex autoimmunity (pqac-00000001, pqac-00000008, pqac-00000013) |
| Mortality and long-term outcome | HP:0003819 Recurrent infection; HP:0001699 Sudden death not usually applicable; no ideal single HPO term | In the UK cohort, 2/40 patients (5%) had died; one death was directly attributed to complement-deficiency-associated fulminant pneumococcal meningitis in infancy, one to intercurrent COVID-19. Most surviving patients can remain well with vaccination, prophylactic antibiotics, and emergency planning; e.g., a C7-deficient patient remained free of further meningitis over 10 years after preventive management (pqac-00000004, pqac-00000007, pqac-00000003) | Lifelong risk, greatest once exposed to pathogenic Neisseria; can begin in infancy/childhood (pqac-00000004, pqac-00000007) | Prognosis improves substantially with diagnosis and prevention, but acute episodes may be fatal or ICU-level severe (pqac-00000004, pqac-00000007, pqac-00000016) | Quality-of-life burden derives from recurrent life-threatening infection risk, repeated vaccination/antibiotic regimens, emergency planning, and family screening obligations; preventive care can markedly reduce recurrence (pqac-00000003, pqac-00000016) |


*Table: This table summarizes the main clinical manifestations and laboratory phenotypes of late/terminal complement component deficiency (C5-C9), with HPO suggestions, frequencies, onset patterns, and mechanistic notes. It is useful for phenotype curation and clinical knowledge-base population.*