Complement C5–C9 deficiency (MAC defects)

Overview

Complement C5-C9 deficiency encompasses a group of rare inherited immune disorders affecting the terminal complement pathway. The complement system is part of the innate immune response - a network of proteins in the blood that works to identify and destroy invading microorganisms. These proteins normally assemble in a precise sequence to form the membrane attack complex (MAC), which creates pores in bacterial cell walls, leading to their destruction.

When any of the complement components C5, C6, C7, C8, or C9 is deficient or non-functional, the MAC cannot form properly. This leaves affected individuals vulnerable to certain types of bacterial infection, particularly those caused by Neisseria meningitidis (meningococcus) and, to a lesser extent, Neisseria gonorrhoeae. The exact prevalence is not well established, though these deficiencies are recognised as rare worldwide. Some populations, including certain communities in South Africa and Japan, show higher carrier frequencies for specific complement deficiencies.

Symptoms & clinical features

The hallmark clinical feature of complement C5-C9 deficiency is recurrent invasive infections with Neisseria meningitidis, the bacterium responsible for meningococcal meningitis and septicaemia. Affected individuals may experience their first episode of meningococcal disease in adolescence or early adulthood, though onset can occur at any age. These infections may recur multiple times throughout life, whereas most people without complement deficiency experience meningococcal infection only once, if at all.

Meningococcal disease typically presents with sudden onset of fever, severe headache, neck stiffness, photophobia (light sensitivity), confusion, and a characteristic non-blanching rash. Septicaemia may cause fever, chills, rapid breathing, low blood pressure, and widespread organ dysfunction. Some individuals with terminal complement deficiencies experience milder or atypical presentations of meningococcal disease compared to the general population, though severe cases still occur. Between infectious episodes, affected individuals are generally well and show no other signs of immune dysfunction.

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Affected organs

The primary clinical impact involves the central nervous system and bloodstream. Meningococcal meningitis affects the protective membranes surrounding the brain and spinal cord (meninges), causing inflammation that can lead to headache, confusion, seizures, and potentially lasting neurological complications if not promptly treated. Meningococcal septicaemia affects the bloodstream and can rapidly progress to septic shock, involving multiple organ systems including the cardiovascular system, kidneys, and skin. The characteristic purpuric rash results from small blood vessel damage and bleeding into the skin.

Immune cells

Immune system dysfunction

Cellular impact

Mechanism at cellular level

Risks & severity

The lifetime risk of meningococcal disease in individuals with terminal complement deficiencies is estimated to be several hundred to several thousand times higher than in the general population. Research suggests that approximately 50-60% of people with these deficiencies will experience at least one episode of invasive meningococcal infection during their lifetime. Recurrent infections occur in a substantial minority of affected individuals.

Despite the increased frequency of infection, evidence suggests that mortality rates from individual meningococcal episodes may be lower in complement-deficient individuals compared to those with normal complement function, possibly due to less severe inflammatory responses. However, meningococcal disease remains a serious medical emergency requiring urgent treatment. Long-term complications can include hearing loss, neurological impairment, limb loss from tissue necrosis, and psychological effects. The risk of gonococcal infection may also be elevated, though this is less well characterised than meningococcal susceptibility.

Genetic causes

Complement C5-C9 deficiency results from pathogenic variants in the genes encoding the respective complement proteins: C5, C6, C7, C8A, C8B, C8G (encoding different chains of the C8 protein), or C9. These genes provide instructions for producing the terminal complement components that must assemble sequentially to form the membrane attack complex. The normal proteins interact with each other and insert into bacterial membranes, creating channels that disrupt the integrity of the bacterial cell wall, ultimately killing the pathogen.

Pathogenic variants that reduce or eliminate production of functional complement proteins prevent proper MAC assembly. Even when other complement components are present at normal levels, the absence of a single terminal component means the complex cannot complete its formation. This leaves Neisseria bacteria, which are particularly susceptible to complement-mediated killing, able to evade this arm of the immune system. Other immune mechanisms, including antibody-mediated responses and phagocytosis, remain intact but are insufficient on their own to provide complete protection against these encapsulated bacteria.

Inheritance pattern

Terminal complement deficiencies follow an autosomal recessive inheritance pattern. This means an affected individual has inherited two copies of a pathogenic variant (one from each parent) in the same complement gene. Parents of an affected person are typically carriers, possessing one pathogenic variant and one working copy of the gene. Carriers generally produce sufficient complement protein to maintain normal immune function and do not experience increased infection risk.

Each child of two carrier parents has a 25% chance of inheriting both pathogenic variants and being affected, a 50% chance of being a carrier like the parents, and a 25% chance of inheriting two working copies. Siblings of affected individuals have a 50% chance of being carriers. If an affected individual has children with a non-carrier partner, all children will be carriers but none will be affected. Genetic counselling can help families understand these inheritance patterns and discuss testing options for at-risk relatives.

Diagnosis & testing

Diagnosis of terminal complement deficiency is typically suspected when someone experiences recurrent meningococcal infections or a first episode of meningococcal disease with unusual features or in an older age group. Initial screening involves measuring total complement activity through a CH50 (total haemolytic complement) test, which assesses the entire classical complement pathway. In terminal complement deficiencies, the CH50 is typically absent or markedly reduced, whilst earlier complement components (C1-C4) are normal.

Confirmation requires measuring individual complement protein levels (C5, C6, C7, C8, C9) to identify which specific component is deficient. Genetic testing can then identify the underlying pathogenic variants in the corresponding gene. In the UK, genetic testing for complement deficiencies may be arranged through clinical immunology services or clinical genetics departments. Individuals with confirmed or suspected terminal complement deficiency should be referred to specialist immunology services for assessment and management planning. Family members may be offered cascade screening to identify other at-risk relatives who might benefit from preventive measures.

Management & lifestyle

Management focuses on infection prevention and rapid treatment of any infections that do occur. Vaccination against meningococcal bacteria is the cornerstone of prevention. Affected individuals should receive comprehensive meningococcal vaccination covering multiple serogroups (A, C, W, Y, and B), with regular booster doses as immunity may wane more quickly than in the general population. Current UK guidance recommends vaccination against all available meningococcal serogroups for individuals with complement deficiencies, along with vaccinations against other encapsulated bacteria including pneumococcus and Haemophilus influenzae type b.

Some immunology specialists recommend antibiotic prophylaxis - long-term low-dose antibiotics to reduce infection risk - though evidence for this approach is limited and practices vary between centres. Any person with terminal complement deficiency who develops symptoms suggesting meningococcal infection requires urgent medical assessment and should seek immediate hospital care. Provision of emergency antibiotics for home administration at the first sign of possible infection is sometimes considered, though this must be discussed with the specialist team. Close contacts of affected individuals should be aware of the increased infection risk and the importance of urgent medical attention for concerning symptoms. Affected individuals should carry medical alert information documenting their complement deficiency.

UK care pathway

In the UK, individuals with suspected or confirmed complement C5-C9 deficiency are typically managed through specialist immunology services, often in conjunction with clinical genetics when genetic testing is pursued. Referral pathways usually begin with infectious diseases specialists or paediatricians who identify the recurrent infection pattern, though some cases come to attention through family cascade screening. The NHS Genomic Medicine Service may facilitate genetic testing when appropriate, particularly for confirming diagnoses or enabling family screening.

Ongoing care involves regular immunology review to ensure vaccination schedules are maintained, monitor for infections, and adjust preventive strategies as needed. Genetic counselling is available through regional genetics services to help affected individuals and their families understand inheritance patterns, recurrence risks, and testing options for relatives. Coordination between immunology, infectious diseases, and general practice ensures that affected individuals receive timely vaccinations and appropriate responses to infectious episodes.

Related conditions

Terminal complement deficiencies should be distinguished from other complement disorders affecting earlier pathway components, such as C3 deficiency, which causes broader immune dysfunction and susceptibility to a wider range of bacterial infections. Properdin deficiency, an X-linked condition affecting the alternative complement pathway, also increases meningococcal disease risk and may present similarly, though the inheritance pattern differs.

Other conditions causing recurrent meningococcal infections include deficiencies in mannose-binding lectin and other upstream complement components, as well as functional or anatomical asplenia (absent or non-functioning spleen), which increases susceptibility to encapsulated bacteria more broadly. Primary antibody deficiencies can also cause recurrent bacterial infections but typically involve a wider spectrum of pathogens and present with different immunological findings. Accurate diagnosis through complement testing helps distinguish these conditions and guide appropriate management.

Frequently asked questions