Complement Factor I deficiency
Description, Causes and Risk Factors:
Complement factor I deficiency is a disorder that affects the immune system. People with this condition are prone to recurrent infections, including infections of the upper respiratory tract, ears, skin, and urinary tract. They may also contract more serious infections such as pneumonia, meningitis, and sepsis, which may be life-threatening.
Some people with complement factor I deficiency have a kidney disorder called glomerulonephritis with isolated C3 deposits. Complement factor I deficiency can also be associated with autoimmune disorders such as rheumatoid arthritis or systemic lupus erythematosus (SLE). Autoimmune disorders occur when the immune system malfunctions and attacks the body's tissues and organs.
Complement factor I deficiency is a rare disorder; its exact prevalence is unknown. At least 38 cases have been reported in the medical literature.
Complement factor I deficiency is caused by mutations in the CFI gene. This gene provides instructions for making a protein called complement factor I. This protein helps regulate a part of the body's immune response known as the complement system. The complement system is a group of proteins that work together to destroy foreign invaders (such as bacteria and viruses), trigger inflammation, and remove debris from cells and tissues. This system must be carefully regulated so it targets only unwanted materials and does not attack the body's healthy cells. Complement factor I and several related proteins protect healthy cells by preventing activation of the complement system when it is not needed.
Mutations in the CFI gene that cause complement factor I deficiency result in abnormal, nonfunctional, or absent complement factor I. The lack (deficiency) of functional complement factor I protein allows uncontrolled activation of the complement system. The unregulated activity of the complement system decreases blood levels of another complement protein called C3, reducing the immune system's ability to fight infections. In addition, the immune system may malfunction and attack its own tissues, resulting in autoimmune disorders.
This condition is inherited in an autosomal recessive pattern, which means both copies of the gene in each cell have mutations. The parents of an individual with an autosomal recessive condition each carry one copy of the mutated gene, but they typically do not show signs and symptoms of the condition.
Complement deficiencies are relatively rare worldwide, and estimates of prevalence are based on results from screening high-risk populations. Retrospective studies of persons with frequent meningococcal infections report varying prevalence based on geographic location. In populations with recurrent meningococcal infection, the prevalence rate is as high as 30%. Individuals with C1q deficiency have a 93% chance of developing SLE. Similarly, C1rs deficiency has a 57% association with SLE and C4 deficiency has a 75% association with SLE.
: The molecular basis of hereditary complement factor I deficiency is described in two pedigrees. In one pedigree, there were two factor I-deficient siblings, one of whom was asymptomatic and the other suffered from recurrent pyogenic infections. Their factor I mRNA was analyzed by reverse transcription of fibroblast RNA followed by amplification using the polymerase chain reaction. Both siblings were homozygous for the same transversion (adenine to thymine) at nucleotide 1282 in the cDNA. This mutation causes histidine-400 to be replaced by leucine. The altered histidine is a semi-conserved residue within the serine proteinase family, although no function has been ascribed to it. The proband of the second pedigree studied was found to be a compound heterozygote. One allele had the same mutation as the first family, the second allele had a donor splice site mutation that resulted in the deletion of the mRNA encoded in the fifth exon (a low-density lipoprotein receptor domain) from its transcript.
The clinicalmanifestations usually begin in early childhood and consist essentially of severe recurrent pyogenic infections mainly causedby Neisseria meningitidis
, Streptococcus pneumoniae, and Haemophilus influenzae
, as wellas an increased incidence of glomerulonephritis and systemic lupus erythematosuslike illness. Homozygous patients have lowlevels of complement C3 and factor B, reduced levels of factor H and, to a lesser extent, of properdin (P) and the terminalcomplement components. Heterozygous individuals are often asymptomatic and havenormal C3 and factor B values, with plasmaconcentrations of factor I of about 50% ofthe normal range.
One can screen for deficiencies in complement by performing the total serum classic hemolytic complement (CH50) test or the alternative hemolytic complement (AP50) test. The CH50 test specifically tests for deficiencies in the classic pathway by measuring the ability of the patient's serum to lyse antibody-coated sheep erythrocytes. A deficiency in any of the classic proteins results in a CH50 of zero. Similarly, the AP50 tests for alternative pathway activity. Direct measurement of individual serum complement proteins, such as C3 and C4, can also be performed and is helpful in determining the diagnosis.
Dried blood spot samples from newborns, which are already widely used in neonatal screening for selected metabolic diseases, may be employed in the future using reverse phase protein microarrays for determination of complement component C3 levels collected at birth. In one recent study, normal levels of C3 were detected from healthy newborns, while no C3 was documented in sera and dried blood samples from patients who were C3 deficient in C3.
Patients with classic complement pathway deficiencies should be screened for sequelae of immune complex diseases. Urinalysis and a complete blood cell count should be performed on these patients.
No specific imaging studies are indicated. Consider performing a head CT scan prior to a lumbar puncture in a patient thought to have meningitis.
Definitive treatment of complement factor I deficiency requires replacing the missing component of the cascade, either through direct infusion of the protein or through gene therapy. Because neither of these options is currently available, treatment of these patients focuses on managing the sequelae of the particular complement deficiencies.
For many patients, treatment must be focused on eradicating a particular infection, especially with encapsulated organisms such as N meningitidis. In most cases of meningococcal disease, treatment with meningeal doses of a third-generation cephalosporin covers most strains of N meningitidis.
NOTE: The above information is for processing purpose. The information provided herein should not be used during any medical emergency or for the diagnosis or treatment of any medical condition.
DISCLAIMER: This information should not substitute for seeking responsible, professional medical care.
- For other patients, the complement deficiency may manifest as episodic flares of autoimmune diseases; treatment of these patients focuses on immunosuppressive therapy of these diseases.
- Importantly, note that some overlap often exists between an increased susceptibility to infection and the greater tendency to develop autoimmune disease; both of these clinical situations may need to be addressed simultaneously in any one patient.