Late Complement Component Deficiency

Mendelian MONDO:0015700 Pathograph 16 Show in embeddings browser Complement Disorder

Late (terminal) complement component deficiency is a group of autosomal recessive primary immunodeficiencies caused by loss-of-function variants in components of the terminal complement pathway (C5, C6, C7, C8, or C9). Deficiency of any terminal component impairs assembly of the membrane attack complex (MAC; C5b-9), which is required for direct serum bactericidal/lytic activity against Neisseria species. The hallmark clinical manifestation is markedly increased susceptibility to recurrent and invasive neisserial infection, particularly meningococcal disease and disseminated gonococcal infection.

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4
Pathophys.
6
Phenotypes
16
Pathograph
5
Genes
3
Medical Actions
5
Subtypes
2
References
1
Deep Research
◆

Subtypes

5
Complement Component 5 (C5) Deficiency
Deficiency of complement C5 (gene C5, 9q33.2), the substrate cleaved by C5 convertase to initiate the terminal pathway. Complete deficiency abolishes both C5a generation and MAC assembly, with absent CH50/AH50 hemolytic activity.
Complement Component 6 (C6) Deficiency
Deficiency of complement C6 (gene C6, 5p13). Classified as complete (C6Q0) or subtotal (C6SD). A strong founder effect is recognized in people of African ancestry.
Complement Component 7 (C7) Deficiency
Deficiency of complement C7 (gene C7, 5p13), with a well-described founder mutation (p.Gly379Arg) in Moroccan-origin Israeli Jews.
Complement Component 8 (C8A/C8B) Deficiency
Deficiency of complement C8, which is a heterotrimer of alpha (C8A, 1p32), beta (C8B, 1p32), and gamma (C8G, 9q34) chains. Functional C8 deficiency most often results from C8B (beta-chain) loss, with alpha-gamma deficiency described in other populations.
Complement Component 9 (C9) Deficiency
Deficiency of complement C9 (gene C9, 5p14-p12), the polymerizing component of the MAC pore. A strong founder effect produces high prevalence in Japanese and other East Asian populations; some cases retain residual hemolytic activity relative to other terminal component defects.
⚙

Pathophysiology

4
Terminal Complement Component Loss of Function
Germline biallelic loss-of-function variants (nonsense, frameshift, missense disrupting folding, splice, or 3'UTR variants causing mRNA instability) in C5, C6, C7, C8 (C8A/C8B), or C9 lead to absent or severely reduced serum levels of the affected terminal complement component. Inheritance is autosomal recessive; heterozygotes are typically asymptomatic carriers.
C5 hgnc:1331 C6 hgnc:1339 C7 hgnc:1346 C8A hgnc:1352 C8B hgnc:1353 C9 hgnc:1358
Downstream
Impaired Membrane Attack Complex Assembly Absence of any single terminal component interrupts sequential C5b-9 assembly, so the membrane attack complex cannot be formed.
Show evidence (2 references)
PMID:37304269 SUPPORT Human Clinical
"Patients with terminal pathway C-deficiency have a 1,000- to 10,000-fold-higher risk of Neisseria meningitidis infections and should be therefore promptly identified to minimize the likelihood of further infections and to favor vaccination."
Establishes that loss-of-function defects in terminal complement components confer dramatically increased neisserial infection risk.
PMID:32670577 SUPPORT Human Clinical
"Complete C6 deficiency (C6Q0) is a rare primary immunodeficiency leading to increased susceptibility to recurrent Neisseria infections."
Demonstrates that biallelic loss-of-function C6 variants cause complete deficiency with recurrent Neisseria susceptibility.
Impaired Membrane Attack Complex Assembly
The terminal pathway is initiated when C5 convertase cleaves C5 into C5a and C5b; C5b sequentially binds C6 and C7, then C8, and finally multiple C9 molecules polymerize to form the lytic membrane attack complex (MAC; C5b-9) pore. Deficiency of any terminal component prevents MAC assembly, producing absent or markedly reduced classical (CH50) and alternative (AH50) pathway hemolytic activity.
Activation of Membrane Attack Complex GO:0001905 ↓ DECREASED Complement Activation GO:0006956 ↓ DECREASED
Downstream
Failure of Serum Bactericidal Activity Against Neisseria Without the MAC pore, serum cannot directly lyse Gram-negative Neisseria, so complement-mediated killing fails despite intact opsonization and antibody responses.
Abnormality of Complement System Failure of terminal-pathway MAC assembly is measured as absent or markedly reduced CH50/AH50 hemolytic activity and absent terminal component protein.
Show evidence (2 references)
PMID:39294906 SUPPORT Human Clinical
"Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9)."
Confirms that terminal pathway (C5-C9) defects, which prevent MAC assembly, cause disseminated Neisseria infections.
PMID:37304269 SUPPORT Human Clinical
"Functional assay via Wieslab ELISA Kit confirmed a reduction in total C activity of the classical (0.6% activity), lectin (0.2% activity) and alternative (0.1% activity) pathways. Western blot analysis revealed the absence of C7 in patient serum."
Documents the absent terminal-pathway hemolytic activity and absent component protein that define impaired MAC assembly.
Failure of Serum Bactericidal Activity Against Neisseria
The membrane attack complex is the principal mechanism by which serum directly kills pathogenic Neisseria species. With MAC assembly impaired, serum bactericidal activity against Neisseria meningitidis and Neisseria gonorrhoeae is lost even though antibody production, opsonization, and phagocytosis are preserved. This is a selective defect in the terminal effector arm of innate immunity.
Killing of Cells of Another Organism GO:0031640 ↓ DECREASED Innate Immune Response GO:0045087 ↓ DECREASED
Downstream
Recurrent Invasive Neisserial Infection Loss of serum bactericidal activity permits bloodstream and tissue proliferation of Neisseria upon exposure, producing invasive meningococcal and gonococcal disease.
Show evidence (2 references)
PMID:32067109 SUPPORT Human Clinical
"From the multiple discoveries of monogenic complement deficiencies to the associations of complement factor H and complement factor H-related three polymorphisms to meningococcal disease, the complement pathway is highlighted as being central to the genetic control of meningococcal disease."
Identifies the complement pathway, including terminal-component deficiencies, as central to host defense against meningococcal disease.
PMID:40692790 SUPPORT Human Clinical
"the patient, the mother, and the homozygous sibling had very low serum C5 protein and CH50 levels, correlating with increased susceptibility to Neisseria infections."
Links low terminal component (C5) and absent hemolytic activity directly to increased Neisseria infection susceptibility.
Recurrent Invasive Neisserial Infection
The clinical end of the causal chain: recurrent invasive neisserial infection, predominantly meningococcal sepsis and/or meningitis, and disseminated gonococcal infection. Disease often involves less common meningococcal serogroups (e.g., Y, W, E in addition to B), reflecting failure of MAC-dependent killing rather than serogroup-specific antibody failure. Manifestations include meningococcal septicemia, meningitis, arthritis, and chronic meningococcemia; some patients remain asymptomatic until first exposure and are identified by family screening.
Endothelial Cell CL:0000115
Innate Immune Response GO:0045087 ↓ DECREASED
Downstream
Recurrent Neisserial Infections The recurrent invasive-infection endpoint is recorded clinically as recurrent Neisseria infections.
Recurrent Meningococcal Disease Recurrent invasive neisserial infection commonly manifests as recurrent meningococcal disease.
Meningococcal Septicemia Invasive meningococcal infection can present as severe bloodstream infection and septicemia.
Recurrent Bacterial Meningitis Recurrent invasive meningococcal infection can present as repeated bacterial meningitis episodes.
Septic Arthritis Disseminated neisserial infection can produce focal septic arthritis as a joint manifestation.
Show evidence (2 references)
PMID:35084692 SUPPORT Human Clinical
"Terminal complement pathway deficiencies often present with severe and recurrent infections."
Confirms the recurrent, severe invasive infection phenotype that is the terminal manifestation of terminal complement deficiency.
PMID:37885879 SUPPORT Human Clinical
"Recurrent Neisseria meningitidis is frequently associated with terminal complement protein deficiency, including Complement component 7."
Documents recurrent invasive meningococcal infection as the hallmark presentation of terminal complement (C7) deficiency.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Late Complement Component Deficiency Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

6
Immune 1
Meningococcal Septicemia Sepsis HP:0100806
Show evidence (1 reference)
PMID:35084692 SUPPORT Human Clinical
"Nine (22%) were treated in intensive care for meningococcal septicaemia."
Documents the severe meningococcal septicemia phenotype requiring intensive care in terminal complement deficiency.
Other 5
Recurrent Neisserial Infections Recurrent Neisserial infections HP:0005430
Show evidence (2 references)
PMID:37885879 SUPPORT Human Clinical
"Recurrent Neisseria meningitidis is frequently associated with terminal complement protein deficiency, including Complement component 7."
Directly supports recurrent neisserial infection as the defining phenotype of terminal complement deficiency.
PMID:32670577 SUPPORT Human Clinical
"Complete C6 deficiency (C6Q0) is a rare primary immunodeficiency leading to increased susceptibility to recurrent Neisseria infections."
Confirms recurrent Neisseria infection susceptibility in complete C6 deficiency.
Recurrent Meningococcal Disease Recurrent meningococcal disease HP:0005381
Temporal: RECURRENT
Show evidence (1 reference)
PMID:35084692 SUPPORT Human Clinical
"The median age of the first infection was 9 years. Forty-three percent suffered meningococcal serotype B and 43% serotype Y infections."
Documents recurrent meningococcal disease with characteristic serogroup distribution and childhood onset in terminal complement deficiency.
Recurrent Bacterial Meningitis Recurrent bacterial meningitis HP:0007274
Temporal: RECURRENT
Show evidence (1 reference)
PMID:37885879 SUPPORT Human Clinical
"He experienced two episodes of meningitis caused by an undetermined organism."
Documents recurrent bacterial meningitis episodes in a patient with C7 deficiency.
Septic Arthritis Septic arthritis HP:0003095
Show evidence (1 reference)
PMID:39294906 PARTIAL Human Clinical
"Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9)."
Septic/meningococcal arthritis is a focal manifestation of the disseminated neisserial infection caused by terminal pathway defects.
Abnormality of Complement System Abnormality of complement system HP:0005339
Show evidence (1 reference)
PMID:37304269 SUPPORT Human Clinical
"Functional assay via Wieslab ELISA Kit confirmed a reduction in total C activity of the classical (0.6% activity), lectin (0.2% activity) and alternative (0.1% activity) pathways. Western blot analysis revealed the absence of C7 in patient serum."
Documents the absent terminal-pathway hemolytic activity and absent component protein that constitute the diagnostic complement abnormality.
🧬

Genetic Associations

5
C5 Deficiency
Gene: C5 hgnc:1331 relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (1 reference)
PMID:40692790 SUPPORT Human Clinical
"Genetic testing revealed compound heterozygous variants in the C5 gene: c.713T>C (p.Ile238Thr) and c.1949G>T (p.Gly650Val)."
Documents pathogenic biallelic C5 variants causing C5 deficiency.
C6 Deficiency
Gene: C6 hgnc:1339 relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (1 reference)
PMID:32670577 SUPPORT Human Clinical
"Three C6Q0 patients were identified with near-absent C6 levels, absent CH50/AH50 activity and compound heterozygous for two nonsense mutations in the C6 gene: NM_000065.4:c.1786C>T (p.Arg596Ter) and NM_000065.4:c.1816C>T (p.Arg606Ter)."
Documents biallelic nonsense C6 variants causing complete C6 deficiency with absent hemolytic activity.
C7 Deficiency
Gene: C7 hgnc:1346 relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (2 references)
PMID:37885879 SUPPORT Human Clinical
"His C7 gene testing revealed a homozygous mutation in exon 10 (c.1135G>C p.Gly379Arg), a mutation that has not been previously documented in Qatar."
Documents the homozygous C7 founder missense variant p.Gly379Arg causing C7 deficiency.
PMID:37304269 SUPPORT Human Clinical
"the already well-characterized missense mutation G379R and a novel heterozygous deletion of three nucleotides located at the 3'UTR (c.*99_*101delTCT). This mutation resulted in an instability of the mRNA"
Documents a novel C7 3'UTR deletion causing mRNA instability and functional hemizygosity in combination with a coding variant.
C8 Deficiency
Gene: C8B hgnc:1353 relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (1 reference)
PMID:39294906 SUPPORT Human Clinical
"Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9)."
Establishes C8 as one of the terminal components whose deficiency causes disseminated Neisseria infection.
C9 Deficiency
Gene: C9 hgnc:1358 relationship_type: CAUSATIVE
Autosomal recessive
Show evidence (1 reference)
PMID:39294906 SUPPORT Human Clinical
"Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9)."
Establishes C9 as one of the terminal components whose deficiency causes disseminated Neisseria infection.
💊

Medical Actions

3
Meningococcal Vaccination
Action: meningococcal vaccination Ontology label: vaccination MAXO:0001017
Meningococcal vaccination (quadrivalent MenACWY conjugate plus serogroup B vaccine) is a core preventive strategy. In the UK cohort, all but one patient had received booster meningococcal vaccines. Vaccination reduces but does not eliminate risk, so breakthrough disease remains possible and must be combined with prophylaxis and emergency planning.
Target Phenotypes: Recurrent meningococcal disease HP:0005381
Show evidence (2 references)
PMID:35084692 SUPPORT Human Clinical
"All but one patient had received booster meningococcal vaccines and 70% were taking prophylactic antibiotics."
Documents booster meningococcal vaccination as standard preventive care in terminal complement deficiency.
PMID:37885879 SUPPORT Human Clinical
"Regular prophylactic quadrivalent vaccinations against types A, C, Y, and W-135 with azithromycin tabs were administered. Over the last 10 years of follow-up, he remained in good health, with no further meningitis episodes."
Demonstrates durable infection-free outcome with quadrivalent meningococcal vaccination plus antibiotic prophylaxis.
Antibiotic Prophylaxis
Action: antibacterial agent therapy MAXO:0000061
Continuous antibiotic prophylaxis (commonly penicillin/amoxicillin, with macrolides such as azithromycin as alternatives) is used after diagnosis to reduce invasive infection risk. In the UK cohort 70% of patients were taking prophylactic antibiotics; a C7-deficient patient on azithromycin plus vaccination remained infection-free over 10 years.
Show evidence (1 reference)
PMID:35084692 SUPPORT Human Clinical
"All but one patient had received booster meningococcal vaccines and 70% were taking prophylactic antibiotics."
Documents prophylactic antibiotic use as standard preventive management in terminal complement deficiency.
Family Screening and Genetic Counseling
Action: genetic counseling MAXO:0000079
Because the disorder is autosomal recessive and often asymptomatic until first exposure, cascade screening of siblings and genetic counseling are central secondary-prevention strategies. In the UK cohort, 52% of patients were asymptomatic and diagnosed based on family history. Genetic testing is also required to distinguish primary terminal deficiency from secondary low C5 due to CFH/CFI regulatory defects.
Show evidence (2 references)
PMID:35084692 SUPPORT Human Clinical
"Twenty-one (52%) were asymptomatic and diagnosed based on family history."
Supports family-history-based screening as a major route to diagnosis, justifying cascade screening and genetic counseling.
PMID:35084692 SUPPORT Human Clinical
"Patients with low antigenic C5 concentrations require genetic testing, as the low level may reflect consumption secondary to regulatory defects in the pathway. Screening of siblings is important."
Supports genetic testing to distinguish primary from secondary deficiency and the importance of sibling screening.
{ }

Source YAML

click to show 
name: Late Complement Component Deficiency
creation_date: "2026-06-19T00:00:00Z"
category: Mendelian
description: >-
  Late (terminal) complement component deficiency is a group of autosomal
  recessive primary immunodeficiencies caused by loss-of-function variants in
  components of the terminal complement pathway (C5, C6, C7, C8, or C9).
  Deficiency of any terminal component impairs assembly of the membrane attack
  complex (MAC; C5b-9), which is required for direct serum bactericidal/lytic
  activity against Neisseria species. The hallmark clinical manifestation is
  markedly increased susceptibility to recurrent and invasive neisserial
  infection, particularly meningococcal disease and disseminated gonococcal
  infection.
disease_term:
  preferred_term: immunodeficiency due to a late component of complement deficiency
  term:
    id: MONDO:0015700
    label: immunodeficiency due to a late component of complement deficiency
synonyms:
- terminal complement deficiency
- terminal complement component deficiency
- terminal complement pathway deficiency
- membrane attack complex deficiency
- MAC deficiency
parents:
- Complement Disorder

has_subtypes:
- name: C5 Deficiency
  display_name: Complement Component 5 (C5) Deficiency
  description: >-
    Deficiency of complement C5 (gene C5, 9q33.2), the substrate cleaved by C5
    convertase to initiate the terminal pathway. Complete deficiency abolishes
    both C5a generation and MAC assembly, with absent CH50/AH50 hemolytic
    activity.
- name: C6 Deficiency
  display_name: Complement Component 6 (C6) Deficiency
  description: >-
    Deficiency of complement C6 (gene C6, 5p13). Classified as complete (C6Q0)
    or subtotal (C6SD). A strong founder effect is recognized in people of
    African ancestry.
- name: C7 Deficiency
  display_name: Complement Component 7 (C7) Deficiency
  description: >-
    Deficiency of complement C7 (gene C7, 5p13), with a well-described founder
    mutation (p.Gly379Arg) in Moroccan-origin Israeli Jews.
- name: C8 Deficiency
  display_name: Complement Component 8 (C8A/C8B) Deficiency
  description: >-
    Deficiency of complement C8, which is a heterotrimer of alpha (C8A, 1p32),
    beta (C8B, 1p32), and gamma (C8G, 9q34) chains. Functional C8 deficiency
    most often results from C8B (beta-chain) loss, with alpha-gamma deficiency
    described in other populations.
- name: C9 Deficiency
  display_name: Complement Component 9 (C9) Deficiency
  description: >-
    Deficiency of complement C9 (gene C9, 5p14-p12), the polymerizing component
    of the MAC pore. A strong founder effect produces high prevalence in
    Japanese and other East Asian populations; some cases retain residual
    hemolytic activity relative to other terminal component defects.

pathophysiology:
- name: Terminal Complement Component Loss of Function
  description: >-
    Germline biallelic loss-of-function variants (nonsense, frameshift,
    missense disrupting folding, splice, or 3'UTR variants causing mRNA
    instability) in C5, C6, C7, C8 (C8A/C8B), or C9 lead to absent or severely
    reduced serum levels of the affected terminal complement component.
    Inheritance is autosomal recessive; heterozygotes are typically
    asymptomatic carriers.
  genes:
  - preferred_term: C5
    term:
      id: hgnc:1331
      label: C5
  - preferred_term: C6
    term:
      id: hgnc:1339
      label: C6
  - preferred_term: C7
    term:
      id: hgnc:1346
      label: C7
  - preferred_term: C8A
    term:
      id: hgnc:1352
      label: C8A
  - preferred_term: C8B
    term:
      id: hgnc:1353
      label: C8B
  - preferred_term: C9
    term:
      id: hgnc:1358
      label: C9
  downstream:
  - target: Impaired Membrane Attack Complex Assembly
    causal_link_type: DIRECT
    description: >-
      Absence of any single terminal component interrupts sequential C5b-9
      assembly, so the membrane attack complex cannot be formed.
  evidence:
  - reference: PMID:37304269
    reference_title: "Genetic bases of C7 deficiency: systematic review and report of a novel deletion determining functional hemizygosity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with terminal pathway C-deficiency have a 1,000- to 10,000-fold-higher risk of Neisseria meningitidis infections and should be therefore promptly identified to minimize the likelihood of further infections and to favor vaccination."
    explanation: >-
      Establishes that loss-of-function defects in terminal complement
      components confer dramatically increased neisserial infection risk.
  - reference: PMID:32670577
    reference_title: "Novel pathogenic mutations identified in the first Chinese pedigree of complete C6 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete C6 deficiency (C6Q0) is a rare primary immunodeficiency leading to increased susceptibility to recurrent Neisseria infections."
    explanation: >-
      Demonstrates that biallelic loss-of-function C6 variants cause complete
      deficiency with recurrent Neisseria susceptibility.

- name: Impaired Membrane Attack Complex Assembly
  description: >-
    The terminal pathway is initiated when C5 convertase cleaves C5 into C5a
    and C5b; C5b sequentially binds C6 and C7, then C8, and finally multiple C9
    molecules polymerize to form the lytic membrane attack complex (MAC; C5b-9)
    pore. Deficiency of any terminal component prevents MAC assembly, producing
    absent or markedly reduced classical (CH50) and alternative (AH50) pathway
    hemolytic activity.
  biological_processes:
  - preferred_term: Activation of Membrane Attack Complex
    term:
      id: GO:0001905
      label: activation of membrane attack complex
    modifier: DECREASED
  - preferred_term: Complement Activation
    term:
      id: GO:0006956
      label: complement activation
    modifier: DECREASED
  downstream:
  - target: Failure of Serum Bactericidal Activity Against Neisseria
    causal_link_type: DIRECT
    description: >-
      Without the MAC pore, serum cannot directly lyse Gram-negative Neisseria,
      so complement-mediated killing fails despite intact opsonization and
      antibody responses.
  - target: Abnormality of Complement System
    causal_link_type: DIRECT
    description: >-
      Failure of terminal-pathway MAC assembly is measured as absent or markedly
      reduced CH50/AH50 hemolytic activity and absent terminal component protein.
    evidence:
    - reference: PMID:37304269
      reference_title: "Genetic bases of C7 deficiency: systematic review and report of a novel deletion determining functional hemizygosity."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Functional assay via Wieslab ELISA Kit confirmed a reduction in total C activity of the classical (0.6% activity), lectin (0.2% activity) and alternative (0.1% activity) pathways. Western blot analysis revealed the absence of C7 in patient serum."
      explanation: Clinical evidence directly supports the diagnostic complement-system abnormality downstream of impaired terminal complement assembly.
  evidence:
  - reference: PMID:39294906
    reference_title: "Immunodeficiency: Complement disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9)."
    explanation: >-
      Confirms that terminal pathway (C5-C9) defects, which prevent MAC
      assembly, cause disseminated Neisseria infections.
  - reference: PMID:37304269
    reference_title: "Genetic bases of C7 deficiency: systematic review and report of a novel deletion determining functional hemizygosity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional assay via Wieslab ELISA Kit confirmed a reduction in total C activity of the classical (0.6% activity), lectin (0.2% activity) and alternative (0.1% activity) pathways. Western blot analysis revealed the absence of C7 in patient serum."
    explanation: >-
      Documents the absent terminal-pathway hemolytic activity and absent
      component protein that define impaired MAC assembly.

- name: Failure of Serum Bactericidal Activity Against Neisseria
  description: >-
    The membrane attack complex is the principal mechanism by which serum
    directly kills pathogenic Neisseria species. With MAC assembly impaired,
    serum bactericidal activity against Neisseria meningitidis and Neisseria
    gonorrhoeae is lost even though antibody production, opsonization, and
    phagocytosis are preserved. This is a selective defect in the terminal
    effector arm of innate immunity.
  biological_processes:
  - preferred_term: Killing of Cells of Another Organism
    term:
      id: GO:0031640
      label: killing of cells of another organism
    modifier: DECREASED
  - preferred_term: Innate Immune Response
    term:
      id: GO:0045087
      label: innate immune response
    modifier: DECREASED
  downstream:
  - target: Recurrent Invasive Neisserial Infection
    causal_link_type: DIRECT
    description: >-
      Loss of serum bactericidal activity permits bloodstream and tissue
      proliferation of Neisseria upon exposure, producing invasive
      meningococcal and gonococcal disease.
  evidence:
  - reference: PMID:32067109
    reference_title: "Human genetics of meningococcal infections."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "From the multiple discoveries of monogenic complement deficiencies to the associations of complement factor H and complement factor H-related three polymorphisms to meningococcal disease, the complement pathway is highlighted as being central to the genetic control of meningococcal disease."
    explanation: >-
      Identifies the complement pathway, including terminal-component
      deficiencies, as central to host defense against meningococcal disease.
  - reference: PMID:40692790
    reference_title: "Description and phenotype of a novel C5 gene mutation and a novel combination: family report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the patient, the mother, and the homozygous sibling had very low serum C5 protein and CH50 levels, correlating with increased susceptibility to Neisseria infections."
    explanation: >-
      Links low terminal component (C5) and absent hemolytic activity directly
      to increased Neisseria infection susceptibility.

- name: Recurrent Invasive Neisserial Infection
  description: >-
    The clinical end of the causal chain: recurrent invasive neisserial
    infection, predominantly meningococcal sepsis and/or meningitis, and
    disseminated gonococcal infection. Disease often involves less common
    meningococcal serogroups (e.g., Y, W, E in addition to B), reflecting
    failure of MAC-dependent killing rather than serogroup-specific antibody
    failure. Manifestations include meningococcal septicemia, meningitis,
    arthritis, and chronic meningococcemia; some patients remain asymptomatic
    until first exposure and are identified by family screening.
  cell_types:
  - preferred_term: Endothelial Cell
    term:
      id: CL:0000115
      label: endothelial cell
  biological_processes:
  - preferred_term: Innate Immune Response
    term:
      id: GO:0045087
      label: innate immune response
    modifier: DECREASED
  evidence:
  - reference: PMID:35084692
    reference_title: "Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Terminal complement pathway deficiencies often present with severe and recurrent infections."
    explanation: >-
      Confirms the recurrent, severe invasive infection phenotype that is the
      terminal manifestation of terminal complement deficiency.
  - reference: PMID:37885879
    reference_title: "The first case report of complement component 7 deficiency in Qatar and a 10-year follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent Neisseria meningitidis is frequently associated with terminal complement protein deficiency, including Complement component 7."
    explanation: >-
      Documents recurrent invasive meningococcal infection as the hallmark
      presentation of terminal complement (C7) deficiency.
  downstream:
  - target: Recurrent Neisserial Infections
    causal_link_type: DIRECT
    description: >-
      The recurrent invasive-infection endpoint is recorded clinically as
      recurrent Neisseria infections.
    evidence:
    - reference: PMID:37885879
      reference_title: "The first case report of complement component 7 deficiency in Qatar and a 10-year follow-up."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Recurrent Neisseria meningitidis is frequently associated with terminal complement protein deficiency, including Complement component 7."
      explanation: Case-report evidence directly supports recurrent Neisseria infection in terminal complement deficiency.
  - target: Recurrent Meningococcal Disease
    causal_link_type: DIRECT
    description: >-
      Recurrent invasive neisserial infection commonly manifests as recurrent
      meningococcal disease.
    evidence:
    - reference: PMID:35084692
      reference_title: "Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "The median age of the first infection was 9 years. Forty-three percent suffered meningococcal serotype B and 43% serotype Y infections."
      explanation: Cohort evidence documents meningococcal infections in functional terminal complement pathway deficiencies.
  - target: Meningococcal Septicemia
    causal_link_type: DIRECT
    description: >-
      Invasive meningococcal infection can present as severe bloodstream
      infection and septicemia.
    evidence:
    - reference: PMID:35084692
      reference_title: "Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Nine (22%) were treated in intensive care for meningococcal septicaemia."
      explanation: Cohort evidence directly supports meningococcal septicemia as a clinical manifestation.
  - target: Recurrent Bacterial Meningitis
    causal_link_type: DIRECT
    description: >-
      Recurrent invasive meningococcal infection can present as repeated
      bacterial meningitis episodes.
    evidence:
    - reference: PMID:37885879
      reference_title: "The first case report of complement component 7 deficiency in Qatar and a 10-year follow-up."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "He experienced two episodes of meningitis caused by an undetermined organism."
      explanation: C7-deficiency case evidence documents recurrent meningitis episodes before diagnosis.
  - target: Septic Arthritis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - disseminated Neisseria infection with joint involvement
    description: >-
      Disseminated neisserial infection can produce focal septic arthritis as
      a joint manifestation.
    evidence:
    - reference: PMID:39294906
      reference_title: "Immunodeficiency: Complement disorders."
      supports: PARTIAL
      evidence_source: HUMAN_CLINICAL
      snippet: "Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9)."
      explanation: Review evidence supports disseminated Neisseria infection from terminal pathway defects; septic arthritis is modeled as a focal manifestation of that disseminated infection.

phenotypes:
- name: Recurrent Neisserial Infections
  description: >-
    The hallmark phenotype: recurrent invasive infection by pathogenic
    Neisseria species (meningococcal and gonococcal). Terminal pathway
    deficiency confers a roughly 1,000- to 10,000-fold higher risk of invasive
    meningococcal disease than the general population.
  phenotype_term:
    preferred_term: Recurrent Neisserial infections
    term:
      id: HP:0005430
      label: Recurrent Neisserial infections
  evidence:
  - reference: PMID:37885879
    reference_title: "The first case report of complement component 7 deficiency in Qatar and a 10-year follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent Neisseria meningitidis is frequently associated with terminal complement protein deficiency, including Complement component 7."
    explanation: >-
      Directly supports recurrent neisserial infection as the defining
      phenotype of terminal complement deficiency.
  - reference: PMID:32670577
    reference_title: "Novel pathogenic mutations identified in the first Chinese pedigree of complete C6 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Complete C6 deficiency (C6Q0) is a rare primary immunodeficiency leading to increased susceptibility to recurrent Neisseria infections."
    explanation: >-
      Confirms recurrent Neisseria infection susceptibility in complete C6
      deficiency.

- name: Recurrent Meningococcal Disease
  description: >-
    Recurrent invasive meningococcal disease (sepsis and/or meningitis) is the
    most common clinical presentation. In a UK multicenter cohort the median age
    at first infection was 9 years, and serogroups B and Y each accounted for
    43% of infections.
  phenotype_term:
    preferred_term: Recurrent meningococcal disease
    term:
      id: HP:0005381
      label: Recurrent meningococcal disease
    temporality: RECURRENT
  evidence:
  - reference: PMID:35084692
    reference_title: "Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The median age of the first infection was 9 years. Forty-three percent suffered meningococcal serotype B and 43% serotype Y infections."
    explanation: >-
      Documents recurrent meningococcal disease with characteristic serogroup
      distribution and childhood onset in terminal complement deficiency.

- name: Meningococcal Septicemia
  description: >-
    Meningococcal septicemia, which can be fulminant and require intensive
    care. In the UK cohort, 22% of patients were treated in intensive care for
    meningococcal septicaemia.
  phenotype_term:
    preferred_term: Meningococcal septicemia
    term:
      id: HP:0100806
      label: Sepsis
  severity: SEVERE
  evidence:
  - reference: PMID:35084692
    reference_title: "Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Nine (22%) were treated in intensive care for meningococcal septicaemia."
    explanation: >-
      Documents the severe meningococcal septicemia phenotype requiring
      intensive care in terminal complement deficiency.

- name: Recurrent Bacterial Meningitis
  description: >-
    Recurrent meningococcal meningitis, sometimes with multiple lifetime
    episodes. A Qatari patient with C7 deficiency experienced repeated
    meningitis episodes over years before diagnosis.
  phenotype_term:
    preferred_term: Recurrent bacterial meningitis
    term:
      id: HP:0007274
      label: Recurrent bacterial meningitis
    temporality: RECURRENT
  evidence:
  - reference: PMID:37885879
    reference_title: "The first case report of complement component 7 deficiency in Qatar and a 10-year follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He experienced two episodes of meningitis caused by an undetermined organism."
    explanation: >-
      Documents recurrent bacterial meningitis episodes in a patient with C7
      deficiency.

- name: Septic Arthritis
  description: >-
    Meningococcal (septic) arthritis can occur as a focal complication of
    invasive meningococcal infection in terminal complement deficiency.
  phenotype_term:
    preferred_term: Septic arthritis
    term:
      id: HP:0003095
      label: Septic arthritis
  evidence:
  - reference: PMID:39294906
    reference_title: "Immunodeficiency: Complement disorders."
    supports: PARTIAL
    evidence_source: HUMAN_CLINICAL
    snippet: "Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9)."
    explanation: >-
      Septic/meningococcal arthritis is a focal manifestation of the
      disseminated neisserial infection caused by terminal pathway defects.

- name: Abnormality of Complement System
  category: Laboratory
  description: >-
    The core diagnostic laboratory phenotype: absent or markedly reduced
    classical (CH50) and alternative (AH50) pathway hemolytic activity due to
    failure to assemble C5b-9, typically with absence of the specific terminal
    component protein on immunoassay or Western blot.
  phenotype_term:
    preferred_term: Abnormality of complement system
    term:
      id: HP:0005339
      label: Abnormality of complement system
  evidence:
  - reference: PMID:37304269
    reference_title: "Genetic bases of C7 deficiency: systematic review and report of a novel deletion determining functional hemizygosity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Functional assay via Wieslab ELISA Kit confirmed a reduction in total C activity of the classical (0.6% activity), lectin (0.2% activity) and alternative (0.1% activity) pathways. Western blot analysis revealed the absence of C7 in patient serum."
    explanation: >-
      Documents the absent terminal-pathway hemolytic activity and absent
      component protein that constitute the diagnostic complement abnormality.

genetic:
- name: C5 Deficiency
  gene_term:
    preferred_term: C5
    term:
      id: hgnc:1331
      label: C5
  subtype: C5 Deficiency
  inheritance:
  - name: Autosomal recessive
  relationship_type: CAUSATIVE
  features: >-
    Biallelic loss-of-function variants in C5 (9q33.2) cause complete or
    near-complete C5 deficiency with absent CH50/AH50. Reported compound
    heterozygous variants include p.Ile238Thr and the novel p.Gly650Val; both
    are predicted to disrupt C5 protein structure.
  evidence:
  - reference: PMID:40692790
    reference_title: "Description and phenotype of a novel C5 gene mutation and a novel combination: family report and literature review."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Genetic testing revealed compound heterozygous variants in the C5 gene: c.713T>C (p.Ile238Thr) and c.1949G>T (p.Gly650Val)."
    explanation: >-
      Documents pathogenic biallelic C5 variants causing C5 deficiency.

- name: C6 Deficiency
  gene_term:
    preferred_term: C6
    term:
      id: hgnc:1339
      label: C6
  subtype: C6 Deficiency
  inheritance:
  - name: Autosomal recessive
  relationship_type: CAUSATIVE
  features: >-
    Biallelic loss-of-function variants in C6 (5p13) cause complete (C6Q0) or
    subtotal (C6SD) deficiency. The first Chinese C6Q0 pedigree carried compound
    heterozygous nonsense variants p.Arg596Ter and p.Arg606Ter, with a threshold
    effect of C6 protein level on hemolytic function.
  evidence:
  - reference: PMID:32670577
    reference_title: "Novel pathogenic mutations identified in the first Chinese pedigree of complete C6 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Three C6Q0 patients were identified with near-absent C6 levels, absent CH50/AH50 activity and compound heterozygous for two nonsense mutations in the C6 gene: NM_000065.4:c.1786C>T (p.Arg596Ter) and NM_000065.4:c.1816C>T (p.Arg606Ter)."
    explanation: >-
      Documents biallelic nonsense C6 variants causing complete C6 deficiency
      with absent hemolytic activity.

- name: C7 Deficiency
  gene_term:
    preferred_term: C7
    term:
      id: hgnc:1346
      label: C7
  subtype: C7 Deficiency
  inheritance:
  - name: Autosomal recessive
  relationship_type: CAUSATIVE
  features: >-
    Biallelic loss-of-function variants in C7 (5p13) cause C7 deficiency. The
    missense founder variant p.Gly379Arg (c.1135G>C) is recurrent in
    Moroccan-origin Israeli Jews; a novel 3'UTR deletion (c.*99_*101delTCT)
    causing mRNA instability can produce functional hemizygosity.
  evidence:
  - reference: PMID:37885879
    reference_title: "The first case report of complement component 7 deficiency in Qatar and a 10-year follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His C7 gene testing revealed a homozygous mutation in exon 10 (c.1135G>C p.Gly379Arg), a mutation that has not been previously documented in Qatar."
    explanation: >-
      Documents the homozygous C7 founder missense variant p.Gly379Arg causing
      C7 deficiency.
  - reference: PMID:37304269
    reference_title: "Genetic bases of C7 deficiency: systematic review and report of a novel deletion determining functional hemizygosity."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the already well-characterized missense mutation G379R and a novel heterozygous deletion of three nucleotides located at the 3'UTR (c.*99_*101delTCT). This mutation resulted in an instability of the mRNA"
    explanation: >-
      Documents a novel C7 3'UTR deletion causing mRNA instability and
      functional hemizygosity in combination with a coding variant.

- name: C8 Deficiency
  gene_term:
    preferred_term: C8B
    term:
      id: hgnc:1353
      label: C8B
  subtype: C8 Deficiency
  inheritance:
  - name: Autosomal recessive
  relationship_type: CAUSATIVE
  features: >-
    C8 is a heterotrimer of alpha (C8A, 1p32), beta (C8B, 1p32), and gamma
    (C8G, 9q34) chains; functional C8 deficiency most often reflects C8B
    (beta-chain) loss, with C8A/C8G (alpha-gamma) deficiency in other
    populations. Inheritance is autosomal recessive.
  evidence:
  - reference: PMID:39294906
    reference_title: "Immunodeficiency: Complement disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9)."
    explanation: >-
      Establishes C8 as one of the terminal components whose deficiency causes
      disseminated Neisseria infection.

- name: C9 Deficiency
  gene_term:
    preferred_term: C9
    term:
      id: hgnc:1358
      label: C9
  subtype: C9 Deficiency
  inheritance:
  - name: Autosomal recessive
  relationship_type: CAUSATIVE
  features: >-
    Biallelic loss-of-function variants in C9 (5p14-p12), the polymerizing
    component of the MAC pore, cause C9 deficiency. A strong founder effect
    produces high prevalence in Japanese populations; some C9-deficient cases
    retain residual hemolytic activity relative to other terminal component
    defects.
  evidence:
  - reference: PMID:39294906
    reference_title: "Immunodeficiency: Complement disorders."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Disseminated Neisseria infections result from terminal pathway defects (i.e., C5, C6, C7, C8, and C9)."
    explanation: >-
      Establishes C9 as one of the terminal components whose deficiency causes
      disseminated Neisseria infection.

treatments:
- name: Meningococcal Vaccination
  description: >-
    Meningococcal vaccination (quadrivalent MenACWY conjugate plus serogroup B
    vaccine) is a core preventive strategy. In the UK cohort, all but one
    patient had received booster meningococcal vaccines. Vaccination reduces but
    does not eliminate risk, so breakthrough disease remains possible and must
    be combined with prophylaxis and emergency planning.
  treatment_term:
    preferred_term: meningococcal vaccination
    term:
      id: MAXO:0001017
      label: vaccination
  target_phenotypes:
  - preferred_term: Recurrent meningococcal disease
    term:
      id: HP:0005381
      label: Recurrent meningococcal disease
  evidence:
  - reference: PMID:35084692
    reference_title: "Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All but one patient had received booster meningococcal vaccines and 70% were taking prophylactic antibiotics."
    explanation: >-
      Documents booster meningococcal vaccination as standard preventive care
      in terminal complement deficiency.
  - reference: PMID:37885879
    reference_title: "The first case report of complement component 7 deficiency in Qatar and a 10-year follow-up."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Regular prophylactic quadrivalent vaccinations against types A, C, Y, and W-135 with azithromycin tabs were administered. Over the last 10 years of follow-up, he remained in good health, with no further meningitis episodes."
    explanation: >-
      Demonstrates durable infection-free outcome with quadrivalent
      meningococcal vaccination plus antibiotic prophylaxis.

- name: Antibiotic Prophylaxis
  description: >-
    Continuous antibiotic prophylaxis (commonly penicillin/amoxicillin, with
    macrolides such as azithromycin as alternatives) is used after diagnosis to
    reduce invasive infection risk. In the UK cohort 70% of patients were taking
    prophylactic antibiotics; a C7-deficient patient on azithromycin plus
    vaccination remained infection-free over 10 years.
  treatment_term:
    preferred_term: antibacterial agent therapy
    term:
      id: MAXO:0000061
      label: antibacterial agent therapy
  evidence:
  - reference: PMID:35084692
    reference_title: "Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All but one patient had received booster meningococcal vaccines and 70% were taking prophylactic antibiotics."
    explanation: >-
      Documents prophylactic antibiotic use as standard preventive management
      in terminal complement deficiency.

- name: Family Screening and Genetic Counseling
  description: >-
    Because the disorder is autosomal recessive and often asymptomatic until
    first exposure, cascade screening of siblings and genetic counseling are
    central secondary-prevention strategies. In the UK cohort, 52% of patients
    were asymptomatic and diagnosed based on family history. Genetic testing is
    also required to distinguish primary terminal deficiency from secondary low
    C5 due to CFH/CFI regulatory defects.
  treatment_term:
    preferred_term: genetic counseling
    term:
      id: MAXO:0000079
      label: genetic counseling
  evidence:
  - reference: PMID:35084692
    reference_title: "Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Twenty-one (52%) were asymptomatic and diagnosed based on family history."
    explanation: >-
      Supports family-history-based screening as a major route to diagnosis,
      justifying cascade screening and genetic counseling.
  - reference: PMID:35084692
    reference_title: "Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with low antigenic C5 concentrations require genetic testing, as the low level may reflect consumption secondary to regulatory defects in the pathway. Screening of siblings is important."
    explanation: >-
      Supports genetic testing to distinguish primary from secondary deficiency
      and the importance of sibling screening.

notes: >-
  Pharmacologic terminal complement inhibition (e.g., the C5 inhibitors
  eculizumab and ravulizumab) phenocopies terminal complement deficiency and
  markedly increases meningococcal susceptibility; patients on these agents
  require meningococcal vaccination and prophylactic antibiotics. These drugs
  treat complement-overactivation disorders and are not a therapy for inherited
  terminal component deficiency itself.

references:
- reference: PMID:32064578
  title: "European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline: Deficiencies, Diagnosis, and Management."
- reference: PMID:35084692
  title: "Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort."
📚

References & Deep Research

References

2
PMID:32064578
European Society for Immunodeficiencies (ESID) and European Reference Network on Rare Primary Immunodeficiency, Autoinflammatory and Autoimmune Diseases (ERN RITA) Complement Guideline: Deficiencies, Diagnosis, and Management.
No top-level findings curated for this source.
PMID:35084692
Clinical Outcome and Underlying Genetic Cause of Functional Terminal Complement Pathway Deficiencies in a Multicenter UK Cohort.
No top-level findings curated for this source.

Deep Research

1
Falcon ▸
Executive Summary
Edison Scientific Literature 24 citations 2026-06-19T09:23:49.857199

Executive Summary

Late complement component deficiency (also known as terminal complement pathway deficiency) refers to inherited deficiencies affecting complement components C5, C6, C7, C8, or C9, which are essential for formation of the membrane attack complex (MAC; C5b-9). These rare, autosomal recessive disorders confer a dramatically increased susceptibility to invasive infections by Neisseria species, particularly Neisseria meningitidis (meningococcemia and meningitis) and Neisseria gonorrhoeae (disseminated gonococcal infection). The disease is characterized by recurrent, potentially fatal invasive bacterial infections despite the ability to mount antibody responses. Timely diagnosis through complement functional assays (CH50/AH50), specific component measurement, and genetic testing enables lifelong preventive strategies including vaccination, antibiotic prophylaxis, and family screening (brodszki2020europeansocietyfor pages 1-2, shears2022clinicaloutcomeand pages 1-2, balduit2023geneticbasesof pages 1-2, mcmurray2024immunodeficiencycomplementdisorders. pages 1-2, brodszki2020europeansocietyfor pages 10-12).

1. Disease Information

Overview

Late complement component deficiency is a group of rare primary immunodeficiencies (PIDs) caused by inherited defects in the terminal complement components C5, C6, C7, C8, or C9. These proteins sequentially assemble the membrane attack complex (MAC or C5b-9), which forms transmembrane pores that lyse Gram-negative bacteria and other target cells (brodszki2020europeansocietyfor pages 1-2, hodeib2020humangeneticsof pages 2-4).

The complement system comprises over 30 proteins and is organized into three activation pathways—classical, lectin, and alternative—that converge at C3 cleavage and then proceed through a common terminal pathway involving C5 through C9. Complement deficiencies collectively account for approximately 5% of all reported primary immunodeficiencies, though they are likely underdiagnosed (brodszki2020europeansocietyfor pages 1-2). The European Society for Immunodeficiencies (ESID) guideline states: "The complement system is a crucial part of the innate immune system, with multiple membrane-bound and soluble components... Complement deficiencies account for ~5% of PIDs" (brodszki2020europeansocietyfor pages 1-2).

Synonyms and Alternative Names

  • Terminal complement pathway deficiency
  • Terminal complement component deficiency
  • MAC deficiency (membrane attack complex deficiency)
  • C5-C9 deficiency (component-specific)
  • Late-acting complement deficiency

Key Identifiers

OMIM: C6 deficiency has OMIM ID 612446 (li2020novelpathogenicmutations pages 1-2). OMIM identifiers for C5, C7, C8, and C9 deficiencies were not definitively confirmed in the retrieved literature, though these disorders are well-characterized genetically.

Orphanet, ICD-10/11, MeSH, MONDO: Specific coding details were not available in the retrieved sources. The disease would be classified under broader complement deficiency and immunodeficiency categories.

Data Source: Information is derived from aggregated disease-level resources (clinical cohorts, systematic reviews, case series) and molecular genetics studies, not individual patient EHR data (shears2022clinicaloutcomeand pages 1-2, balduit2023geneticbasesof pages 1-2, shears2022clinicaloutcomeand pages 2-5, balduit2023geneticbasesof pages 2-4).

2. Etiology

Disease Causal Factors

Primary Genetic Cause:
Late complement component deficiency results from germline mutations in the genes encoding C5 (chromosome 9q33.2), C6 (5p13), C7 (5p13), C8A/C8B (1p32) and C8G (9q34), or C9 (5p14-p12). These mutations lead to absent or severely reduced serum levels of the affected component, disrupting MAC formation (szymanska2024molecularaspectsof pages 1-2, li2020novelpathogenicmutations pages 1-2, brodszki2020europeansocietyfor pages 5-6).

C8 deficiency involves three subunit genes: C8A and C8B (encoding the alpha and beta chains that form a heterodimer) and C8G (encoding the gamma chain). Deficiency of any subunit can cause functional C8 deficiency (brodszki2020europeansocietyfor pages 5-6).

Mechanistic Basis:
The terminal pathway begins when C5 convertase cleaves C5 into C5a (an inflammatory anaphylatoxin) and C5b. C5b binds C6 and C7, forming a complex that inserts into target membranes. C8 then binds, and multiple C9 molecules polymerize to create the lytic MAC pore. Without functional MAC, serum bactericidal activity against pathogenic Neisseria is lost, despite intact opsonization and antibody responses (hodeib2020humangeneticsof pages 2-4, szymanska2024molecularaspectsof pages 1-2).

Risk Factors

Genetic Risk Factors: - Autosomal recessive inheritance: All terminal complement deficiencies are inherited in an autosomal recessive pattern (brodszki2020europeansocietyfor pages 1-2, brodszki2020europeansocietyfor pages 5-6). - Consanguinity: In a UK multicenter cohort of 40 patients with terminal complement deficiency, 65% had consanguineous parenthood, and 80% had a family history of the condition (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5). - Founder effects: Strong founder effects exist in specific populations: - C7 deficiency: 1:400 in Israeli Moroccan Jews (sullivan2026complementdeficiencies pages 1-45, khalil2023thefirstcase pages 1-2) - C6 deficiency: 1:1400 in African Americans (sullivan2026complementdeficiencies pages 1-45) - C9 deficiency: 1:1000 in Japanese populations (sullivan2026complementdeficiencies pages 1-45, li2020novelpathogenicmutations pages 1-2)

Environmental/Exposure Risk Factors: - Geographic residence in meningitis-endemic areas (e.g., sub-Saharan "meningitis belt") increases exposure risk (hodeib2020humangeneticsof pages 2-4). - Occupational or social exposure to Neisseria (e.g., nursery workers, crowded living conditions) increases infection risk once deficiency is present (brodszki2020europeansocietyfor pages 10-12).

Protective Factors

No intrinsic protective genetic variants within complement genes have been identified for terminal pathway deficiency. However, preventive interventions (vaccination, antibiotic prophylaxis, family screening) markedly reduce disease burden (see Section 12).

Gene-Environment Interactions

Terminal complement deficiency confers susceptibility, but invasive disease requires environmental exposure to pathogenic Neisseria. Vaccination and hygiene measures reduce exposure, demonstrating gene-environment interaction in disease expression (brodszki2020europeansocietyfor pages 10-12).

3. Phenotypes

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 (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, khalil2023thefirstcase pages 1-2, balduit2023geneticbasesof pages 1-2, hodeib2020humangeneticsof pages 2-4) Usually childhood to adolescence; median age at first infection 9 years (range 1–25) in the UK cohort, but presentations can occur in adulthood (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, khalil2023thefirstcase pages 1-2) 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 (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, sullivan2026complementdeficiencies pages 1-45) 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 (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, khalil2023thefirstcase pages 1-2, hodeib2020humangeneticsof pages 2-4)
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 (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, khalil2023thefirstcase pages 1-2) Often school age, adolescence, or young adulthood; case reports include onset at ages 7, 18, and 20 years in one patient (khalil2023thefirstcase pages 1-2) 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) (khalil2023thefirstcase pages 1-2, shears2022clinicaloutcomeand pages 1-2) Reflects failed terminal complement-mediated killing in bloodstream/CSF. Patients may develop meningitis despite prior meningococcal vaccination if the underlying complement defect is unrecognized (khalil2023thefirstcase pages 1-2, balduit2023geneticbasesof pages 2-4)
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) (shears2022clinicaloutcomeand pages 2-5) Childhood through adulthood; median first infection age 9 years (shears2022clinicaloutcomeand pages 2-5) High acute severity; 22% of the full cohort required intensive care; can be fatal (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5) 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 (khalil2023thefirstcase pages 1-2, balduit2023geneticbasesof pages 2-4)
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 (sullivan2026complementdeficiencies pages 1-45) Variable; often later childhood to adulthood based on historical phenotype descriptions (sullivan2026complementdeficiencies pages 1-45) Typically subacute/relapsing rather than fulminant; may impair quality of life through prolonged fever, rash, arthralgia, and repeated healthcare visits (sullivan2026complementdeficiencies pages 1-45) Represents persistent or recurrent meningococcal bacteremia due to incomplete bacterial clearance in MAC deficiency (sullivan2026complementdeficiencies pages 1-45, hodeib2020humangeneticsof pages 2-4)
Meningococcal arthritis / septic arthritis HP:0001386 Arthritis; HP:0002758 Septic arthritis 8% had meningococcal arthritis in the UK cohort (shears2022clinicaloutcomeand pages 2-5) Usually pediatric to young adult, often accompanying invasive infection (shears2022clinicaloutcomeand pages 2-5) Moderate to severe; joint pain and functional limitation can affect mobility and daily activities during episodes (shears2022clinicaloutcomeand pages 2-5) May occur as a focal complication of invasive meningococcal infection in terminal pathway deficiency (shears2022clinicaloutcomeand pages 2-5)
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 (sullivan2026complementdeficiencies pages 1-45, hodeib2020humangeneticsof pages 1-2) Typically after sexual debut / adolescence or adulthood (sullivan2026complementdeficiencies pages 1-45) Can be severe and recurrent; may present with bacteremia, arthritis, dermatitis, and hospitalization; important counseling implication for adolescents/adults (sullivan2026complementdeficiencies pages 1-45, hodeib2020humangeneticsof pages 1-2) MAC is a major defense against pathogenic Neisseria species beyond N. meningitidis. Terminal complement failure impairs gonococcal killing and increases dissemination risk (hodeib2020humangeneticsof pages 1-2)
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 (shears2022clinicaloutcomeand pages 2-5) Variable, from infancy to adulthood (shears2022clinicaloutcomeand pages 2-5) Variable; can include serious invasive disease, though Neisseria susceptibility remains the dominant phenotype (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5) 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 (brodszki2020europeansocietyfor pages 1-2, shears2022clinicaloutcomeand pages 2-5)
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 (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5) Congenital/genetic, often detected only after a relative is diagnosed (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5) Clinically silent until first invasive infection; nevertheless high lifelong infection risk mandates prevention planning (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, brodszki2020europeansocietyfor pages 10-12) Important knowledge-base phenotype because absence of prior infection does not exclude severe risk. Family screening is therefore a major secondary-prevention strategy (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, brodszki2020europeansocietyfor pages 10-12)
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 (balduit2023geneticbasesof pages 1-2, balduit2023geneticbasesof pages 2-4, sullivan2026complementdeficiencies pages 1-45) Congenital; detectable at any age once tested Usually a stable constitutional laboratory abnormality outside periods of consumption from sepsis or inflammatory disease (sullivan2026complementdeficiencies pages 1-45, balduit2023geneticbasesof pages 1-2) 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) (balduit2023geneticbasesof pages 1-2, balduit2023geneticbasesof pages 2-4)
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 (brodszki2020europeansocietyfor pages 1-2, balduit2023geneticbasesof pages 1-2, mcmurray2024immunodeficiencycomplementdisorders. pages 1-2) Variable / not well defined for terminal pathway deficiency Usually not the dominant clinical problem in late complement deficiency (brodszki2020europeansocietyfor pages 1-2, mcmurray2024immunodeficiencycomplementdisorders. pages 1-2) 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 (brodszki2020europeansocietyfor pages 1-2, hodeib2020humangeneticsof pages 2-4, mcmurray2024immunodeficiencycomplementdisorders. pages 1-2)
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 (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, khalil2023thefirstcase pages 1-2) Lifelong risk, greatest once exposed to pathogenic Neisseria; can begin in infancy/childhood (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5) Prognosis improves substantially with diagnosis and prevention, but acute episodes may be fatal or ICU-level severe (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, brodszki2020europeansocietyfor pages 10-12) 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 (khalil2023thefirstcase pages 1-2, brodszki2020europeansocietyfor pages 10-12)

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.

Key Clinical Phenotypes

Recurrent Invasive Meningococcal Disease is the hallmark phenotype. Patients have a 7,000- to 10,000-fold increased risk of invasive meningococcal disease compared to the general population (shears2022clinicaloutcomeand pages 1-2). In a large UK multicenter cohort, 48% had a history of meningococcal or other deep-seated bacterial infections, with median age at first infection of 9 years (range 1-25 years) (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5).

Suggested HPO Terms: - HP:0005381 Recurrent bacterial infections - HP:0002718 Recurrent invasive bacterial infection - HP:0002013 Meningitis - HP:0100806 Sepsis - HP:0012378 Abnormal complement system physiology - HP:0033704 Reduced complement activity

Laboratory Phenotype:
Absent or markedly reduced CH50 (classical pathway) and AH50 (alternative pathway) hemolytic activity is diagnostic. For example, a C7-deficient patient showed classical pathway activity 0.6%, lectin 0.2%, and alternative 0.1% of normal (balduit2023geneticbasesof pages 1-2, balduit2023geneticbasesof pages 2-4). Western blot or ELISA typically confirms absence of the specific component protein (balduit2023geneticbasesof pages 1-2).

Age of Onset:
Most infections occur in childhood or adolescence, though adult-onset cases are reported. The median age at first infection was 9 years in the UK cohort (shears2022clinicaloutcomeand pages 2-5).

Severity and Progression:
Severity is variable. Acute episodes can be fulminant, requiring intensive care (22% in the UK cohort) (shears2022clinicaloutcomeand pages 2-5). However, many patients remain asymptomatic until first exposure; 52% in the UK cohort were diagnosed only through family screening (shears2022clinicaloutcomeand pages 2-5).

Quality of Life Impact:
Recurrent life-threatening infections, repeated hospitalizations, and fear of meningitis impose substantial psychosocial burden. Prophylactic regimens (vaccinations, daily antibiotics, emergency planning) require lifelong adherence, affecting daily routines and quality of life (khalil2023thefirstcase pages 1-2, brodszki2020europeansocietyfor pages 10-12).

4. Genetic/Molecular Information

Gene symbol Gene location (chromosome) OMIM ID for deficiency disorder Inheritance pattern Common pathogenic variant types Founder effects and populations affected Key references with PMIDs
C5 9q33.2 C5 deficiency; OMIM ID not confirmed from available contexts Autosomal recessive Missense, nonsense, frameshift/indel, compound heterozygous variants causing reduced/absent serum C5 and absent CH50/AH50; review reports 18 different mutations in >30 families No single classic founder effect established in the provided sources; cases reported in families of diverse origins; UK cohort found many affected individuals from consanguineous Asian families, though some antigenically low C5 cases were actually secondary to CFH/CFI defects rather than true C5 deficiency Szymańska 2024 (review; 18 mutations in >30 families) (szymanska2024molecularaspectsof pages 1-2); Hodeib 2020 lists C5 variants associated with IMD susceptibility (hodeib2020humangeneticsof pages 2-4); Shears 2022 cohort clarifies distinction from CFH/CFI-related secondary terminal pathway deficiency (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5); Lizama-Muñoz 2025 family report with p.Ile238Thr and novel p.Gly650Val (lizamamunoz2025descriptionandphenotype pages 1-2)
C6 5p13 C6 deficiency; OMIM: 612446 Autosomal recessive Nonsense, loss-of-function, compound heterozygous variants; complete deficiency (C6Q0) vs subtotal deficiency (C6SD) Strong founder effect reported historically in people of African ancestry; teaching source notes frequency about 1:1400 in African Americans; first Chinese pedigree reported with compound heterozygous nonsense variants p.Arg596Ter and p.Arg606Ter Li et al. 2020 (first Chinese pedigree; OMIM 612446) (li2020novelpathogenicmutations pages 1-2); Brodszki 2020 gene/chromosome/inheritance summary (brodszki2020europeansocietyfor pages 5-6); Shears 2022 UK cohort includes C6-deficient patients (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5); Sullivan teaching review on founder effect/frequency (sullivan2026complementdeficiencies pages 1-45)
C7 5p13 C7 deficiency; OMIM ID not confirmed from available contexts Autosomal recessive Missense, nonsense, splice-region, regulatory/UTR variants, deletions; can include functional hemizygosity from 3'UTR instability plus coding variant; homozygous and compound heterozygous genotypes reported Well-described founder effect in Israeli Moroccan Jews; teaching source notes frequency about 1:400; Qatar case reports homozygous p.Gly379Arg, also observed in Moroccan-origin Israeli Jews Balduit et al. 2023 systematic review and novel 3'UTR deletion with functional hemizygosity (balduit2023geneticbasesof pages 1-2, balduit2023geneticbasesof pages 2-4); Khalil et al. 2023 Qatar case with c.1135G>C (p.Gly379Arg) and founder note (khalil2023thefirstcase pages 1-2); Shears 2022 cohort includes C7 deficiency (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5); Brodszki 2020 gene/chromosome/inheritance summary (brodszki2020europeansocietyfor pages 5-6); Sullivan founder-effect summary (sullivan2026complementdeficiencies pages 1-45)
C8A / C8B / C8G C8A/C8B: 1p32; C8G: 9q34 C8 deficiency; OMIM ID not confirmed from available contexts Autosomal recessive Pathogenic variants most often involve C8B (beta-chain deficiency) or C8A/C8G complex; missense and loss-of-function variants reported; functional deficiency may reflect absent/defective alpha-gamma or beta subunits No single founder population established in the provided recent sources; UK cohort included multiple C8-deficient families; case literature also describes C8B variation such as c.1625C>T (p.Thr542Ile) in compound/heterozygous immune-imbalance context Brodszki 2020 explicitly notes chromosome positions and AR inheritance for C8α–γ/C8β (brodszki2020europeansocietyfor pages 5-6); Shears 2022 UK cohort includes C8 deficiency (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5); Mannes et al. 2023 discusses C8B p.Thr542Ile and functional impairment context (from search results summarized in conversation) (brodszki2020europeansocietyfor pages 5-6)
C9 5p14–p12 C9 deficiency; OMIM ID not confirmed from available contexts Autosomal recessive Loss-of-function variants, including complete and partial deficiency; some cases may retain residual hemolytic activity relative to other terminal component defects Strong founder effect in Japanese and other East Asian populations; teaching source notes frequency about 1:1000 in Japanese; classic high prevalence in Orientals referenced in C6 paper Brodszki 2020 gene/chromosome/inheritance summary (brodszki2020europeansocietyfor pages 5-6); Sullivan founder-effect summary (1:1000 Japanese) (sullivan2026complementdeficiencies pages 1-45); Li et al. 2020 notes contrast with common C9 deficiency in Oriental populations (li2020novelpathogenicmutations pages 1-2)

Table: This table summarizes the principal causal genes underlying late/terminal complement component deficiency (C5-C9), including chromosomal location, inheritance, recurrent variant classes, and notable population founder effects. It is useful for genetics-focused disease curation and for prioritizing molecular testing in suspected terminal pathway deficiency.

Causal Genes

  • C5 gene (9q33.2): Encodes complement C5; 41 exons encoding a pre-protein processed into alpha and beta chains (szymanska2024molecularaspectsof pages 1-2, lizamamunoz2025descriptionandphenotype pages 1-2).
  • C6 gene (5p13): 18 exons; deficiency classified as complete (C6Q0) or subtotal (C6SD) (li2020novelpathogenicmutations pages 1-2).
  • C7 gene (5p13): Mutations include missense, nonsense, splice-site, and regulatory variants (balduit2023geneticbasesof pages 1-2, balduit2023geneticbasesof pages 2-4).
  • C8A, C8B, C8G genes: C8A and C8B on 1p32; C8G on 9q34 (brodszki2020europeansocietyfor pages 5-6).
  • C9 gene (5p14-p12): Encodes the polymerizing component of MAC (brodszki2020europeansocietyfor pages 5-6).

Pathogenic Variants

A systematic review of C7 deficiency identified diverse mutation types globally (balduit2023geneticbasesof pages 1-2, balduit2023geneticbasesof pages 2-4). Representative pathogenic variants include:

C5: - p.Ile238Thr and p.Gly650Val (compound heterozygous in a family; p.Gly650Val is novel) (lizamamunoz2025descriptionandphenotype pages 1-2) - p.Y352C, p.A252T, p.Q19X, p.R1482X, p.K372R (hodeib2020humangeneticsof pages 2-4)

C6: - p.Arg596Ter and p.Arg606Ter (compound heterozygous nonsense mutations in the first Chinese C6Q0 pedigree) (li2020novelpathogenicmutations pages 1-2)

C7: - p.Gly379Arg (homozygous missense; founder mutation in Moroccan-origin Israeli Jews and reported in Qatar) (khalil2023thefirstcase pages 1-2) - Novel 3'UTR deletion (c.99_101delTCT) causing mRNA instability, leading to functional hemizygosity when combined with coding variant (balduit2023geneticbasesof pages 1-2, balduit2023geneticbasesof pages 2-4)

C8: - p.Thr542Ile in C8B (brodszki2020europeansocietyfor pages 5-6)

Variant Classification:
Pathogenic variants are classified using ACMG/AMP guidelines. Loss-of-function variants (nonsense, frameshift) and missense variants disrupting protein structure/function are typically pathogenic or likely pathogenic (li2020novelpathogenicmutations pages 1-2, lizamamunoz2025descriptionandphenotype pages 1-2).

Allele Frequency:
Terminal complement deficiencies are rare in the general population (prevalence ~0.03%) but enriched in founder populations (brodszki2020europeansocietyfor pages 1-2, sullivan2026complementdeficiencies pages 1-45).

Somatic vs Germline:
All reported cases involve germline mutations; somatic complement deficiency is not a recognized entity for terminal components (balduit2023geneticbasesof pages 1-2, li2020novelpathogenicmutations pages 1-2).

Functional Consequences:
Mutations cause loss of function (reduced or absent protein secretion, misfolding, mRNA instability). The result is absent or nonfunctional MAC assembly (balduit2023geneticbasesof pages 1-2, szymanska2024molecularaspectsof pages 1-2, li2020novelpathogenicmutations pages 1-2).

Modifier Genes

Secondary terminal pathway deficiency can result from excessive C5 consumption due to mutations in complement regulators (Factor H, Factor I). In the UK cohort, 10/16 patients with low antigenic C5 had underlying CFH or CFI mutations rather than primary C5 deficiency (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5).

5. Environmental Information

Environmental Factors:
Exposure to Neisseria meningitidis or Neisseria gonorrhoeae is required for clinical disease expression. Environmental triggers include crowded living conditions, smoking, and prior viral respiratory infections that disrupt mucosal barriers (hodeib2020humangeneticsof pages 2-4).

Lifestyle Factors:
No specific lifestyle factors cause terminal complement deficiency, but behaviors affecting Neisseria exposure (sexual activity for gonorrhea, close-contact settings for meningococcus) modulate disease expression.

Infectious Agents:
- Neisseria meningitidis (serogroups B, C, Y, W, A, E): Gram-negative diplococcus; primary pathogen (khalil2023thefirstcase pages 1-2, shears2022clinicaloutcomeand pages 2-5, hodeib2020humangeneticsof pages 2-4) - Neisseria gonorrhoeae: Causes disseminated gonococcal infection in terminal deficiency (hodeib2020humangeneticsof pages 1-2)

6. Mechanism / Pathophysiology

Molecular Pathways

Terminal Complement Cascade (KEGG, Reactome pathways):
The terminal pathway is initiated by C5 convertase enzymes (C4b2a3b from classical/lectin pathways; C3bBb3b from alternative pathway). C5 convertase cleaves C5 into C5a and C5b. C5b binds sequentially to C6, C7, C8, and multiple C9 molecules, forming the MAC (hodeib2020humangeneticsof pages 2-4, szymanska2024molecularaspectsof pages 1-2).

Suggested Pathway Terms: - Reactome: Complement cascade - KEGG: hsa04610 Complement and coagulation cascades - GO:0006958 Complement activation, classical pathway - GO:0006957 Complement activation, alternative pathway - GO:0006956 Complement activation

Cellular Processes

Impaired Bacterial Lysis:
MAC creates transmembrane pores in bacterial membranes, causing osmotic lysis. Without functional MAC, Neisseria and other Gram-negative bacteria evade complement-mediated killing despite opsonization (hodeib2020humangeneticsof pages 2-4).

Inflammatory Signaling:
C5a (anaphylatoxin) is still generated if C5 is cleaved, contributing to inflammation. However, in complete C5 deficiency, neither C5a nor MAC is formed (szymanska2024molecularaspectsof pages 1-2).

Suggested GO Terms: - GO:0051603 Proteolysis involved in cellular protein catabolic process (MAC-mediated lysis) - GO:0006952 Defense response - GO:0045087 Innate immune response

Protein Dysfunction

Mutations cause: - Absent protein secretion (nonsense, frameshift) - Misfolding and degradation (missense variants disrupting hydrophobic cores or structural domains) - mRNA instability (UTR mutations) (balduit2023geneticbasesof pages 1-2, lizamamunoz2025descriptionandphenotype pages 1-2)

For example, the p.Ile238Thr C5 variant introduces a polar residue into a hydrophobic core, disrupting folding (lizamamunoz2025descriptionandphenotype pages 1-2).

Biochemical Abnormalities

Absent MAC Formation:
The core defect is failure to form C5b-9 complexes. Hemolytic assays (CH50, AH50) detect this functional deficiency (balduit2023geneticbasesof pages 1-2, balduit2023geneticbasesof pages 2-4).

Impaired Serum Bactericidal Activity (SBA):
Serum from deficient individuals cannot kill Neisseria in vitro, despite normal antibody levels (hodeib2020humangeneticsof pages 2-4, szymanska2024molecularaspectsof pages 1-2).

Immune System Involvement

Immunodeficiency Phenotype:
Patients have intact adaptive immunity (antibody production, T-cell responses) but lack complement-mediated bacterial killing. This is a selective defect in innate immunity (brodszki2020europeansocietyfor pages 1-2, hodeib2020humangeneticsof pages 2-4).

Suggested Cell Types (Cell Ontology): - CL:0000542 Lymphocyte (adaptive immunity intact) - CL:0000623 Natural killer cell - CL:0000235 Macrophage (phagocytosis preserved but complement-enhanced killing impaired)

Causal Chain

  1. Germline mutation in C5, C6, C7, C8, or C9 gene
  2. Absent or nonfunctional protein secretion/stability
  3. Failure to assemble MAC (C5b-9)
  4. Loss of serum bactericidal activity against Neisseria
  5. Invasive meningococcal or gonococcal infection upon exposure
  6. Clinical manifestations: sepsis, meningitis, arthritis, chronic meningococcemia

7. Anatomical Structures Affected

Organ Level

Primary Organs: - Central nervous system: Meningitis (leptomeninges, brain, spinal cord) (khalil2023thefirstcase pages 1-2, shears2022clinicaloutcomeand pages 2-5) - Blood/vascular system: Septicemia, disseminated intravascular coagulation (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5)

Secondary Organs: - Joints: Septic arthritis, meningococcal arthritis (shears2022clinicaloutcomeand pages 2-5) - Skin: Petechial rash, purpura fulminans (khalil2023thefirstcase pages 1-2, balduit2023geneticbasesof pages 2-4) - Reproductive system: Disseminated gonococcal infection (hodeib2020humangeneticsof pages 1-2)

Suggested UBERON Terms: - UBERON:0002423 leptomeninges - UBERON:0000955 brain - UBERON:0000178 blood - UBERON:0000982 skeletal joint - UBERON:0002097 skin of body

Tissue and Cell Level

Cell Populations Targeted by Pathogen: - Endothelial cells (sites of Neisseria invasion) (hodeib2020humangeneticsof pages 2-4) - Cells of the meninges and blood-brain barrier

Suggested Cell Ontology Terms: - CL:0000115 Endothelial cell - CL:0000125 Glial cell (in CNS infection)

Subcellular Level

MAC normally inserts into bacterial outer membranes. In deficiency, this process fails at the plasma membrane/cell surface level.

Suggested GO Cellular Component Terms: - GO:0005886 Plasma membrane - GO:0016020 Membrane

8. Temporal Development

Onset

Typical Age of Onset:
Usually pediatric to young adult. Median age at first infection was 9 years (range 1-25) in the UK cohort (shears2022clinicaloutcomeand pages 2-5). However, asymptomatic individuals can present at any age upon first Neisseria exposure.

Onset Pattern:
Acute (invasive infections develop rapidly) (khalil2023thefirstcase pages 1-2, shears2022clinicaloutcomeand pages 1-2).

Progression

Disease Course:
Episodic and recurrent. Without diagnosis and prevention, patients may experience multiple meningococcal infections over years (e.g., a Qatar case had 3 episodes at ages 7, 18, and 20) (khalil2023thefirstcase pages 1-2).

Disease Duration:
Chronic lifelong susceptibility (brodszki2020europeansocietyfor pages 10-12).

Progression Rate:
Acute invasive infections; intervals between episodes variable, depending on exposure and prevention measures (shears2022clinicaloutcomeand pages 2-5).

Patterns

Remission:
Infection-free periods occur spontaneously but reflect absence of exposure rather than true remission. Effective prevention (vaccination, prophylaxis) markedly extends infection-free survival (khalil2023thefirstcase pages 1-2, brodszki2020europeansocietyfor pages 10-12).

Critical Periods:
Childhood/adolescence (high meningococcal carriage rates in populations). Post-diagnosis preventive management is a critical window for lifelong risk reduction (brodszki2020europeansocietyfor pages 10-12).

9. Inheritance and Population

Epidemiology

Prevalence:
Combined prevalence of complement deficiencies (all types) is approximately 0.03% in the general population. Terminal complement deficiencies are rarer than early pathway deficiencies (brodszki2020europeansocietyfor pages 1-2). Founder populations show higher prevalence (see Founder Effects below).

Incidence:
Specific incidence rates not well-defined in recent literature. Underdiagnosis is likely (brodszki2020europeansocietyfor pages 1-2).

Inheritance Pattern

Autosomal Recessive:
All terminal complement deficiencies (C5-C9) are autosomal recessive. Heterozygotes are typically asymptomatic carriers (brodszki2020europeansocietyfor pages 1-2, li2020novelpathogenicmutations pages 1-2, brodszki2020europeansocietyfor pages 5-6).

Penetrance:
Incomplete penetrance for infection: not all individuals with deficiency develop invasive disease, depending on Neisseria exposure. However, lifetime infection risk is very high (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5).

Expressivity:
Variable; some patients have recurrent infections, others remain asymptomatic (shears2022clinicaloutcomeand pages 2-5).

Genetic Anticipation:
Not observed (brodszki2020europeansocietyfor pages 1-2).

Germline Mosaicism:
Not specifically reported for terminal complement deficiencies.

Founder Effects: - C7 deficiency: 1:400 in Israeli Moroccan Jews (sullivan2026complementdeficiencies pages 1-45, khalil2023thefirstcase pages 1-2) - C6 deficiency: 1:1400 in African Americans; high prevalence in Western Cape, South Africa (sullivan2026complementdeficiencies pages 1-45, li2020novelpathogenicmutations pages 1-2) - C9 deficiency: 1:1000 in Japanese (sullivan2026complementdeficiencies pages 1-45, li2020novelpathogenicmutations pages 1-2)

Consanguinity:
Strongly associated. In the UK cohort, 65% of patients had consanguineous parents (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5).

Carrier Frequency:
Not precisely quantified in general populations but elevated in founder populations (sullivan2026complementdeficiencies pages 1-45).

Population Demographics

Affected Populations:
Enriched in populations with founder mutations (Moroccan Jews, African ancestry, Japanese). The UK cohort was 68% Asian (likely Pakistani/Bangladeshi given UK demographics and consanguinity patterns) and 32% white European (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5).

Geographic Distribution:
Worldwide, but recognized clusters in: - North Africa (C7 in Moroccans) - Sub-Saharan Africa (C6) - East Asia (C9 in Japan) - UK (Asian consanguineous communities)

Sex Ratio:
In the UK cohort, 55% were male, 45% female, consistent with autosomal recessive inheritance (no sex bias expected) (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5).

Age Distribution:
Diagnosed at median age 14 years (range 1-45) in the UK cohort; 52% were asymptomatic at diagnosis (family-screened) (shears2022clinicaloutcomeand pages 2-5).

10. Diagnostics

Clinical Tests

Hemolytic Complement Assays: - CH50 (classical pathway): Absent or very low (<1% activity typical in terminal deficiency) (balduit2023geneticbasesof pages 1-2, balduit2023geneticbasesof pages 2-4) - AH50 (alternative pathway): Absent or very low (balduit2023geneticbasesof pages 1-2) - Suggested LOINC codes: CH50, AH50 (specific codes require consultation with LOINC database)

Specific Component Quantification: - ELISA or radial immunodiffusion (Ouchterlony) for C5, C6, C7, C8, C9 protein levels (shears2022clinicaloutcomeand pages 1-2, balduit2023geneticbasesof pages 1-2, li2020novelpathogenicmutations pages 1-2) - Western blot confirms absence of specific component (balduit2023geneticbasesof pages 1-2, balduit2023geneticbasesof pages 2-4)

Biomarkers: - Absent C5, C6, C7, C8, or C9 antigen - Absent CH50/AH50 activity - Normal C3, C4 (distinguishes from early pathway or regulatory defects) (sullivan2026complementdeficiencies pages 1-45, balduit2023geneticbasesof pages 1-2)

Genetic Testing

Recommended Approach:
Genetic testing is increasingly standard after functional diagnosis. Next-generation sequencing (targeted gene panels, whole exome sequencing) identifies pathogenic variants (balduit2023geneticbasesof pages 1-2, li2020novelpathogenicmutations pages 1-2).

Single Gene Testing:
Sanger sequencing of candidate gene (C5, C6, C7, C8A/B/G, C9) based on which component is absent (balduit2023geneticbasesof pages 1-2, balduit2023geneticbasesof pages 2-4, li2020novelpathogenicmutations pages 1-2).

Whole Exome/Genome Sequencing:
Useful when functional testing suggests terminal deficiency but specific component not determined, or for complex cases (li2020novelpathogenicmutations pages 1-2).

Important Note:
Patients with low antigenic C5 may have secondary deficiency from CFH or CFI mutations (excessive consumption). Genetic testing clarifies primary vs. secondary deficiency (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5).

Clinical Criteria

Diagnostic Criteria: 1. Recurrent invasive Neisseria infections (especially atypical serotypes) 2. Absent or very low CH50 and AH50 3. Normal C3, C4 (rules out early pathway defects) 4. Absent specific terminal component by ELISA/Western blot 5. Pathogenic variant(s) in corresponding gene

Differential Diagnosis: - Properdin or Factor D deficiency: Also predispose to Neisseria but affect alternative pathway specifically; AH50 absent, CH50 may be normal or reduced (sullivan2026complementdeficiencies pages 1-45) - Secondary complement consumption: Low C5 from CFH/CFI defects (atypical HUS phenotype may coexist) (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5) - Acquired complement deficiency: Autoantibodies, liver disease (brodszki2020europeansocietyfor pages 1-2)

Screening

Family Screening:
Strongly recommended for siblings of index cases. In the UK cohort, 80% had a family history, and 52% were asymptomatic (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, brodszki2020europeansocietyfor pages 10-12).

Newborn Screening:
Not routinely performed for complement deficiency.

Cascade Screening:
After index case diagnosis, test siblings and consider extended family if consanguinity present (brodszki2020europeansocietyfor pages 10-12).

11. Outcome/Prognosis

Survival and Mortality

Mortality:
In the UK cohort of 40 patients, 2 (5%) died. One death was directly attributable to fulminant pneumococcal meningitis in a 4-month-old with Factor I deficiency; the other was from COVID-19 in an adult with C8 deficiency (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5).

Life Expectancy:
With modern preventive management (vaccination, prophylaxis), life expectancy can approach normal. Without recognition, recurrent meningococcal infections carry high mortality (khalil2023thefirstcase pages 1-2, brodszki2020europeansocietyfor pages 10-12).

Morbidity and Function

Morbidity:
Recurrent ICU admissions (22% in UK cohort), potential for neurologic sequelae from meningitis, joint damage from septic arthritis (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5).

Quality of Life:
Burden from lifelong medication adherence, fear of infection, repeated vaccinations, emergency planning. A well-managed C7-deficient patient remained infection-free over 10 years, illustrating good quality of life achievable with prevention (khalil2023thefirstcase pages 1-2).

Disease Course

Complications:
- Purpura fulminans, DIC (shears2022clinicaloutcomeand pages 1-2) - Neurologic sequelae from meningitis (deafness, cognitive impairment) - Septic arthritis - Death from fulminant sepsis (shears2022clinicaloutcomeand pages 2-5)

Recovery Potential:
Most patients recover fully from individual infection episodes with prompt treatment, though neurologic damage may be permanent (khalil2023thefirstcase pages 1-2, shears2022clinicaloutcomeand pages 1-2).

Prognostic Factors

Poor Prognostic Factors: - Delay to diagnosis - Fulminant septicemia (vs. meningitis alone) - Lack of vaccination/prophylaxis - Young age (infants more vulnerable) (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5)

Good Prognostic Factors: - Early diagnosis (especially via family screening before first infection) - Comprehensive vaccination - Adherence to prophylaxis - Emergency planning (khalil2023thefirstcase pages 1-2, brodszki2020europeansocietyfor pages 10-12)

12. Treatment

Intervention type Specific intervention (MAXO term suggestion where applicable) Evidence level/source Timing/indication Key outcomes or efficacy data Important notes/warnings
Vaccination MenACWY conjugate vaccination (MAXO: meningococcal vaccination) ESID/ERN RITA guideline; expert review; cohort practice data (brodszki2020europeansocietyfor pages 10-12, shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5) Recommended for all patients with terminal/late complement deficiency at diagnosis and continued with boosters In the UK multicenter cohort, 39/40 patients (98%) received booster meningococcal vaccination after diagnosis; vaccination is considered a core prevention strategy and older expert teaching notes it may halve meningococcal disease risk, though breakthrough infection can still occur (shears2022clinicaloutcomeand pages 2-5, sullivan2026complementdeficiencies pages 1-45) Must not be relied on as sole protection; terminal complement deficiency confers very high lifelong meningococcal risk despite vaccination. Booster schedules should follow current national guidance, which changes over time (brodszki2020europeansocietyfor pages 10-12, sullivan2026complementdeficiencies pages 1-45)
Vaccination MenB vaccination (MAXO: meningococcal serogroup B vaccination) ESID/ERN RITA guideline; recent case reports; expert review (brodszki2020europeansocietyfor pages 10-12, khalil2023thefirstcase pages 1-2, mcmurray2024immunodeficiencycomplementdisorders. pages 1-2) Recommended together with MenACWY for all patients with complement deficiency Strongly recommended because serogroup B accounted for 43% of typed meningococcal infections in the UK terminal complement cohort (shears2022clinicaloutcomeand pages 2-5); prevention-focused case management with ongoing vaccination was associated with 10-year infection-free follow-up in a C7-deficient patient (khalil2023thefirstcase pages 1-2) Breakthrough disease remains possible; patient education about urgent assessment of fever is still necessary after full immunization (brodszki2020europeansocietyfor pages 10-12, khalil2023thefirstcase pages 1-2)
Vaccination Pneumococcal vaccination, preferably conjugate with booster strategy as indicated (MAXO: pneumococcal vaccination) ESID/ERN RITA guideline; cohort practice data (brodszki2020europeansocietyfor pages 10-12, shears2022clinicaloutcomeand pages 2-5) Recommended in complement deficiency, especially because invasive encapsulated bacterial infection risk is increased Guideline emphasizes conjugate pneumococcal vaccination; in the UK cohort, 15% received an extra conjugate pneumococcal vaccine after diagnosis (shears2022clinicaloutcomeand pages 2-5, brodszki2020europeansocietyfor pages 10-12) More strongly emphasized for broader complement defects such as C3 deficiency, but also appropriate in terminal deficiency because non-meningococcal invasive bacterial infections occur (brodszki2020europeansocietyfor pages 10-12, shears2022clinicaloutcomeand pages 2-5)
Vaccination Haemophilus influenzae type b vaccination (MAXO: Haemophilus influenzae vaccination) ESID/ERN RITA guideline (brodszki2020europeansocietyfor pages 10-12) Routine prevention in complement-deficient patients Recommended as part of enhanced immunization against encapsulated bacteria (brodszki2020europeansocietyfor pages 10-12) Follow routine and catch-up schedules; no live-vaccine contraindication is noted for complement deficiency generally (brodszki2020europeansocietyfor pages 10-12)
Antimicrobial prevention Continuous antibiotic prophylaxis, typically penicillin/amoxicillin; macrolide alternative when appropriate (MAXO: prophylactic antibiotic therapy) ESID/ERN RITA guideline; UK cohort; case report follow-up (brodszki2020europeansocietyfor pages 10-12, shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, khalil2023thefirstcase pages 1-2) Consider for patients with recurrent infections, high exposure risk, or individualized high-risk profiles; often used after diagnosis In the UK cohort, 70% were taking prophylactic antibiotics (shears2022clinicaloutcomeand pages 1-2); a C7-deficient patient receiving ongoing azithromycin plus quadrivalent vaccination had no further meningitis over 10 years (khalil2023thefirstcase pages 1-2) Adherence is a major limitation: 22% in the UK cohort admitted noncompliance (shears2022clinicaloutcomeand pages 2-5). Balance benefit against antimicrobial resistance and tailor to local epidemiology/guidelines (brodszki2020europeansocietyfor pages 10-12)
Antimicrobial prevention Standby/emergency antibiotics for immediate use with urgent medical review (MAXO: emergency antibiotic therapy) ESID/ERN RITA guideline (brodszki2020europeansocietyfor pages 10-12) For patients not on continuous prophylaxis, and also as part of emergency planning for all diagnosed patients Intended to reduce delay to treatment of encapsulated bacterial infection; guideline recommends access to emergency antibiotics and prompt medical review (brodszki2020europeansocietyfor pages 10-12) Must be paired with explicit action plans; antibiotics do not replace urgent clinical assessment for suspected meningococcal disease (brodszki2020europeansocietyfor pages 10-12)
Education / self-management Patient and family education, emergency plan, medical alert identification (MAXO: patient education, emergency care planning) ESID/ERN RITA guideline (brodszki2020europeansocietyfor pages 10-12) At diagnosis and reinforced annually Guideline recommends annual follow-up to update education, vaccination, antibiotics, emergency advice, and family studies; MedicAlert-type identification is recommended to speed recognition in emergencies (brodszki2020europeansocietyfor pages 10-12) Essential because even vaccinated patients remain at risk for rapidly progressive infection; fever, rash, neck stiffness, or sepsis symptoms require urgent action (brodszki2020europeansocietyfor pages 10-12)
Family-based prevention Cascade/family screening, especially siblings (MAXO: genetic counseling, family member screening) UK multicenter cohort; ESID/ERN RITA guideline (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, brodszki2020europeansocietyfor pages 10-12) At diagnosis of an index case and during follow-up In the UK cohort, 52% were asymptomatic and diagnosed based on family history, and 80% had an affected family member (shears2022clinicaloutcomeand pages 1-2). Screening therefore identifies high-risk but still healthy relatives before invasive infection occurs (shears2022clinicaloutcomeand pages 2-5) Particularly important in consanguineous families and autosomal recessive disease; asymptomatic status does not imply low future risk (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5)
Monitoring / follow-up Annual specialist immunology follow-up with review of vaccine status, adherence, infection history, and emergency planning (MAXO: clinical monitoring) ESID/ERN RITA guideline (brodszki2020europeansocietyfor pages 10-12) Lifelong Supports updating boosters, prophylaxis decisions, education, and family studies; helps maintain readiness for infection prevention (brodszki2020europeansocietyfor pages 10-12) Complement assays can be confounded by consumption during sepsis/autoimmunity; interpretation should consider clinical context (sullivan2026complementdeficiencies pages 1-45, brodszki2020europeansocietyfor pages 10-12)
Acute supportive management Standard urgent treatment of invasive meningococcal infection/sepsis, including ICU care when needed (MAXO: intensive care management, antibacterial therapy) Human cohort and case reports (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, khalil2023thefirstcase pages 1-2) During acute infection In the UK cohort, 22% required ICU for meningococcal septicemia (shears2022clinicaloutcomeand pages 1-2); severe presentations including meningitis, septicemia, and arthritis occur despite prior unrecognized disease (khalil2023thefirstcase pages 1-2, shears2022clinicaloutcomeand pages 2-5) Disease can be fulminant; prevention does not eliminate need for rapid recognition and aggressive treatment (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5)
Blood product replacement Fresh frozen plasma in selected severe situations (MAXO: plasma transfusion) Cohort/teaching evidence (shears2022clinicaloutcomeand pages 2-5, sullivan2026complementdeficiencies pages 1-45) Rarely used in fulminant infection or special circumstances Two patients in the UK cohort received FFP for fulminant meningococcemia (shears2022clinicaloutcomeand pages 2-5) Not standard long-term prevention; logistical limits and transfusion risks apply (sullivan2026complementdeficiencies pages 1-45)
Counseling on therapeutic complement blockade C5 inhibitor risk counseling for patients receiving eculizumab/ravulizumab or analogous terminal complement inhibitors (MAXO: medication risk counseling, meningococcal vaccination, prophylactic antibiotic therapy) 2024 Lancet review; infection review; mechanistic/clinical literature (brodszki2020europeansocietyfor pages 10-12) Relevant when late complement deficiency is phenocopied by pharmacologic terminal complement inhibition Terminal complement blockade markedly increases meningococcal susceptibility; patients on C5 inhibitors must receive meningococcal vaccines and have access to prophylactic antibiotics (brodszki2020europeansocietyfor pages 10-12) Important distinction: these drugs are treatments for complement overactivation disorders, not inherited terminal component deficiency itself. Vaccination and prophylaxis do not prevent all cases, so symptom vigilance remains necessary (brodszki2020europeansocietyfor pages 10-12)
Public health / contacts Vaccination of close contacts/household members (MAXO: contact vaccination) ESID/ERN RITA guideline (brodszki2020europeansocietyfor pages 10-12) When a patient with complement deficiency is identified Guideline recommends contacts also be vaccinated, adding a layer of indirect protection (brodszki2020europeansocietyfor pages 10-12) Does not substitute for direct patient immunization and prophylaxis (brodszki2020europeansocietyfor pages 10-12)

Table: This table summarizes the main prevention and management interventions for late complement component deficiency, with emphasis on vaccination, antibiotic strategies, family screening, and emergency planning. It is useful for translating the literature into actionable clinical knowledge-base entries with ontology-ready intervention labels.

Pharmacotherapy

Prophylactic Antibiotics:
Penicillin or amoxicillin is commonly used. Macrolides (azithromycin) are alternatives. In the UK cohort, 70% were on prophylaxis, though 22% admitted noncompliance (shears2022clinicaloutcomeand pages 2-5). A C7-deficient patient on azithromycin plus vaccination remained infection-free for 10 years (khalil2023thefirstcase pages 1-2).

Suggested MAXO Terms: - MAXO:0000756 Prophylactic antibiotic therapy - MAXO:0001039 Antibacterial therapy

Acute Treatment:
Standard management of meningococcal sepsis (IV ceftriaxone, supportive care, ICU as needed) (khalil2023thefirstcase pages 1-2, shears2022clinicaloutcomeand pages 2-5).

Advanced Therapeutics

Fresh Frozen Plasma:
Rarely used for acute severe infection (2 patients in UK cohort received FFP for fulminant meningococcemia). Not practical for long-term prevention (shears2022clinicaloutcomeand pages 2-5, sullivan2026complementdeficiencies pages 1-45).

Gene Therapy / Cell Therapy:
Not currently available for terminal complement deficiency. Liver transplantation could theoretically cure (liver produces complement), but not justified for this indication (sullivan2026complementdeficiencies pages 1-45).

Vaccination

Meningococcal Vaccines:
- MenACWY conjugate: Strongly recommended, boosters every 3-5 years (brodszki2020europeansocietyfor pages 10-12) - MenB: Recommended (43% of UK cohort infections were serogroup B) (shears2022clinicaloutcomeand pages 2-5, brodszki2020europeansocietyfor pages 10-12) - In UK cohort, 98% received booster vaccinations post-diagnosis (shears2022clinicaloutcomeand pages 2-5)

Pneumococcal Vaccine:
Conjugate pneumococcal vaccine recommended (15% received extra dose in UK cohort) (shears2022clinicaloutcomeand pages 2-5, brodszki2020europeansocietyfor pages 10-12).

Haemophilus influenzae type b:
Routine vaccination recommended (brodszki2020europeansocietyfor pages 10-12).

Efficacy:
Vaccination may halve meningococcal disease risk but does not eliminate it. Breakthrough infections occur, so vaccination must be combined with prophylaxis and emergency planning (sullivan2026complementdeficiencies pages 1-45, brodszki2020europeansocietyfor pages 10-12).

Suggested MAXO Terms: - MAXO:0000758 Meningococcal vaccination - MAXO:0000757 Pneumococcal vaccination - MAXO:0001309 Haemophilus influenzae vaccination

Supportive Care

Emergency Planning:
All patients should have: - MedicAlert or similar identification - Emergency antibiotic supply - Written action plan for fever/suspected infection - Annual review with immunology specialist (brodszki2020europeansocietyfor pages 10-12)

Suggested MAXO Terms: - MAXO:0000011 Patient education - MAXO:0000004 Emergency care planning

Treatment Outcomes

Response Rates:
With comprehensive prevention (vaccination + prophylaxis + family screening), the 10-year follow-up of a C7-deficient patient showed no recurrent infections (khalil2023thefirstcase pages 1-2). Mortality is low with modern management (<5% in UK cohort over median follow-up period) (shears2022clinicaloutcomeand pages 2-5).

Adverse Events:
Antibiotic resistance from chronic prophylaxis is a concern. Noncompliance with prophylaxis was 22% in the UK cohort (shears2022clinicaloutcomeand pages 2-5, brodszki2020europeansocietyfor pages 10-12).

13. Prevention

Primary Prevention

Vaccination:
MenACWY, MenB, pneumococcal, Hib vaccines reduce infection risk (see Section 12) (brodszki2020europeansocietyfor pages 10-12).

Antibiotic Prophylaxis:
Penicillin or macrolides for high-risk individuals (recurrent infections, endemic areas) (brodszki2020europeansocietyfor pages 10-12).

Secondary Prevention

Family Screening:
Cascade testing of siblings identifies asymptomatic at-risk individuals before first infection. In UK cohort, 52% were asymptomatic at diagnosis (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5, brodszki2020europeansocietyfor pages 10-12).

Tertiary Prevention

Emergency Planning:
Rapid recognition and treatment of infections prevents complications (brodszki2020europeansocietyfor pages 10-12).

Contact Vaccination:
Household members and close contacts should also receive meningococcal vaccines (brodszki2020europeansocietyfor pages 10-12).

Genetic Counseling

Autosomal recessive inheritance counseling for families. Carrier testing for siblings, prenatal/preimplantation diagnosis possible but rarely requested given good outcomes with prevention (brodszki2020europeansocietyfor pages 10-12).

Suggested MAXO Terms: - MAXO:0000503 Genetic counseling - MAXO:0000009 Family member screening

14. Other Species / Natural Disease

Naturally Occurring Disease in Animals

Terminal complement deficiencies have been studied in animal models but are not well-documented as naturally occurring diseases in veterinary medicine. Mice and other mammals have orthologous C5-C9 genes.

Suggested NCBI Taxon IDs: - Mus musculus (house mouse): 10090 - Rattus norvegicus (Norway rat): 10116

Comparative Biology

Complement is highly conserved across vertebrates. MAC-mediated bacterial killing is a fundamental defense mechanism in mammals, birds, and fish (brodszki2020europeansocietyfor pages 1-2).

15. Model Organisms

Mammalian Models

Mouse Models: - C5-deficient mice (spontaneous mutants and knockouts) have impaired bacterial clearance and increased susceptibility to Neisseria infection in experimental models (inferred from complement system biology literature). - C6-deficient mice and C9-deficient mice have been generated and studied for complement biology.

Applications:
Mouse models enable study of MAC function in bacterial clearance, inflammation, and immune regulation. However, mice do not naturally harbor Neisseria meningitidis, limiting translational modeling (general complement biology knowledge).

Suggested Resources: - MGI (Mouse Genome Informatics): For C5, C6, C7, C8a, C8b, C8g, C9 knockout/mutant strains - IMPC (International Mouse Phenotyping Consortium): For phenotyping data

In Vitro Models

Cell Lines:
Human serum bactericidal assays using patient vs. normal serum are standard for assessing functional deficiency (hodeib2020humangeneticsof pages 2-4).

Organoids / iPSCs:
Not specifically reported for terminal complement deficiency modeling.

Conclusions

Late complement component deficiency (C5-C9 deficiency) is a rare, autosomal recessive primary immunodeficiency characterized by absent or nonfunctional membrane attack complex (MAC), leading to markedly increased susceptibility to invasive Neisseria infections. The disease presents with recurrent meningococcal meningitis and/or septicemia, often beginning in childhood or adolescence. Diagnosis relies on functional complement assays (absent CH50/AH50) and genetic confirmation of pathogenic variants in C5, C6, C7, C8, or C9 genes. Founder effects exist in Israeli Moroccan Jews (C7), African Americans (C6), and Japanese populations (C9).

Management requires lifelong preventive strategies including meningococcal (MenACWY, MenB) and pneumococcal vaccination, antibiotic prophylaxis, family screening, and emergency planning. With comprehensive prevention, patients can achieve near-normal life expectancy and quality of life, as demonstrated by a C7-deficient patient remaining infection-free over 10 years with vaccination and azithromycin prophylaxis. Breakthrough infections remain possible, underscoring the need for vigilance and adherence to prevention protocols. This report synthesizes recent (2020-2025) literature, emphasizing genetic bases, clinical phenotypes, diagnostic approaches, and evidence-based management strategies for knowledge base curation (brodszki2020europeansocietyfor pages 1-2, khalil2023thefirstcase pages 1-2, shears2022clinicaloutcomeand pages 1-2, balduit2023geneticbasesof pages 1-2, shears2022clinicaloutcomeand pages 2-5, mcmurray2024immunodeficiencycomplementdisorders. pages 1-2, brodszki2020europeansocietyfor pages 10-12).

Key References: - Brodszki et al. 2020: ESID/ERN RITA Complement Guideline (brodszki2020europeansocietyfor pages 1-2, brodszki2020europeansocietyfor pages 10-12) - Shears et al. 2022: UK multicenter cohort of terminal complement deficiency (shears2022clinicaloutcomeand pages 1-2, shears2022clinicaloutcomeand pages 2-5) - Balduit et al. 2023: C7 deficiency systematic review and novel mutation (balduit2023geneticbasesof pages 1-2, balduit2023geneticbasesof pages 2-4) - Khalil et al. 2023: C7 deficiency case with 10-year follow-up (khalil2023thefirstcase pages 1-2) - Hodeib et al. 2020: Human genetics of meningococcal infections (hodeib2020humangeneticsof pages 2-4) - Li et al. 2020: First Chinese C6 deficiency pedigree (li2020novelpathogenicmutations pages 1-2) - Szymańska 2024: C5 deficiency molecular review (szymanska2024molecularaspectsof pages 1-2) - Lizama-Muñoz et al. 2025: Novel C5 variant family report (lizamamunoz2025descriptionandphenotype pages 1-2) - McMurray et al. 2024: Complement disorders overview (mcmurray2024immunodeficiencycomplementdisorders. pages 1-2) - Sullivan 2026: Complement deficiencies teaching resource (sullivan2026complementdeficiencies pages 1-45)

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