Alternative titles; symbols
SNOMEDCT: 234621005; ORPHA: 200418; DO: 0050419;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 4q25 | Complement factor I deficiency | 610984 | Autosomal recessive | 3 | CFI | 217030 |
A number sign (#) is used with this entry because of evidence that complement factor I ('eye') deficiency (CFID) is caused by heterozygous, homozygous, or compound heterozygous mutation in the gene encoding complement factor I (CFI; 217030) on chromosome 4q25.
Hereditary deficiency of complement factor I (CFID) is associated with a propensity to pyogenic infection and usually follows an autosomal recessive pattern of inheritance (Vyse et al., 1996). A subset of patients with CFID develop a renal disease termed 'C3 glomerulopathy' (C3G2), which is characterized by glomerular deposition of C3 observed on renal biopsy. Affected individuals have hematuria and proteinuria with variable progression of renal dysfunction (summary by Servais et al., 2007).
For a discussion of genetic heterogeneity of C3G, see C3G1 (609814), also known as complement factor H deficiency.
Alper et al. (1970, 1970) and Abramson et al. (1971) reported a patient with increased susceptibility to infection and accelerated catabolism of C3 due to deficiency of the C3 inactivator. Alper et al. (1972) demonstrated that the C3 inactivator also acts as an inhibitor in the alternative complement pathway. A study of the family of the patient with 'type I essential hypercatabolism of C3' reported by Alper et al. (1970, 1970) found that a number of relatives had values for the inactivator about 50% of normal. Alper et al. (1972) concluded that the patient was homozygous for an inherited deficiency of the C3 inactivator.
Thompson and Lachmann (1977) reported an affected girl. Vyse et al. (1994, 1996) presented follow-up on this patient. She presented with a history of recurrent infections beginning at age 4 months with bacterial meningitis (Streptococcus pneumoniae) and otitis media. Between ages 7 and 15 years, she had 4 further episodes of meningitis, which on 2 occasions was found to be Neisseria meningitidis. She had no circulating factor I and low C3 (approximately 30% of normal controls). Her mother had about 50% circulating factor I; the father was not available for study.
Vyse et al. (1994) reported 4 cases of complement factor I deficiency from 3 families, including the patient reported by Thompson and Lachmann (1977), bringing the total number of reported cases to 23. In the first family, the proband presented at age 18 months with Staphylococcus epidermidis septic arthritis of the left shoulder. He subsequently had recurrent sinusitis and otitis media, and developed Neisseria meningitis at age 13 years. His older sister had no history of recurrent infections. Both the proband and his sister had no detectable circulating factor I or factor B, and a very low complement C3 level, most of which was in the form of C3B. Both parents had approximately 50% of normal circulating factor I and normal factors B and C3. An affected child in the second family had recurrent pyogenic infections and a self-limiting vasculitic illness. Using radioligand binding assays, Vyse et al. (1994) demonstrated increased binding of C3b to erythrocytes in a patient with factor I deficiency. This C3b could not be cleaved by autologous serum but could be cleaved by normal serum or purified factor I.
Sadallah et al. (1999) reported a patient who had recurrent otitis, sinusitis, and bronchopneumonia since childhood. At age 24 years, he had an acute episode of systemic vasculitis with purpura, but no nephritis. Complement factor I deficiency was diagnosed at age 36 years. Uncontrolled activation of the alternative complement pathway resulted in serum depletion of other complement components, especially C3, which explained the predisposition for pyogenic infections. A progressive loss of renal function accompanied by proteinuria and hematuria started after age 40 years. Renal biopsy showed focal segmental glomerulonephritis with glomerular deposits of immunoglobulins and complement C3 and C4 fragments. In addition, there appeared to be depletion of complement receptor I (CR1; 120620). Sadallah et al. (1999) postulated a link between the factor I deficiency and glomerulonephritis in this patient.
Baracho et al. (2003) reported 2 Brazilian sisters, born of consanguineous parents, with complement factor I deficiency. Both had complete absence of serum factor I and decreased levels of factor H (CFH; 134370), C3, and factor B. The older patient, who was 20 years of age, developed systemic lupus erythematosus (SLE; 152700) and glomerulonephritis, and had several infectious episodes during her childhood. The younger sister developed a severe intestinal infection that evolved to fatal sepsis at age 3 years.
Grumach et al. (2006) reported a large consanguineous Brazilian family in which 3 individuals had complete factor I deficiency and 16 individuals had partial factor I deficiency. Those with complete deficiency had recurrent respiratory infections, skin infections, and meningitis; 1 died from sepsis. All had low serum C3, low factor H, and undetectable factor I activity. Among those with partial factor I deficiency, 10 presented with recurrent infections such as tonsillitis, pneumonia, urinary tract infections, otitis, and meningitis. One each presented with chronic arthritis and rheumatic fever, suggesting autoimmune involvement. Only 2 individuals with partial deficiency did not have recurrent infections. The authors noted that factor I deficiency partially impairs the clearance of immune complexes by phagocytes, increasing the risk for the development of immune complex-mediated diseases. Grumach et al. (2006) concluded that individuals with partial factor I deficiency are also at increased risk for infection and autoimmune disorders and recommended prophylactic treatment with vaccination against encapsulated bacteria and antibiotics.
Servais et al. (2007) described a unique form of glomerulonephritis characterized by isolated mesangial C3 deposits without dense intramembranous deposits or mesangial proliferation, which the authors termed 'glomerulonephritis C3.' Heterozygous mutations in complement regulatory genes were identified in 4 of 6 unrelated patients with glomerulonephritis C3, including 2 patients each with mutations in the CFH (see, e.g., 134370.0017) and CFI (see, e.g., 217030.0007) genes, respectively. The findings indicated that dysregulation of the complement alternative pathway is associated with a wide spectrum of diseases ranging from atypical hemolytic-uremic syndrome (aHUS; 235400) to glomerulonephritis with C3 deposits.
The transmission pattern of CFID in the families reported by Vyse et al. (1994, 1996) was consistent with autosomal recessive inheritance.
In 2 sibs with complement factor I deficiency reported by Vyse et al. (1994), Vyse et al. (1996) identified a homozygous mutation in the CFI gene (217030.0001). Vyse et al. (1996) also determined that the patient originally reported by Thompson and Lachmann (1977) was compound heterozygous for 2 mutations in the CFI gene (217030.0001; 217030.0002).
In 2 Brazilian sisters with complement factor I deficiency, Baracho et al. (2003) identified a homozygous mutation in the CFI gene (217030.0003).
Abramson, N., Alper, C. A., Lachmann, P. J., Rosen, F. S., Jandl, J. H. Deficiency of C3 inactivator in man. J. Immun. 107: 19-27, 1971. [PubMed: 4997111]
Alper, C. A., Abramson, N., Johnston, R. B., Jr., Jandl, J. H., Rosen, F. S. Increased susceptibility to infection associated with abnormalities of complement-mediated functions and of the third component of complement (C3). New Eng. J. Med. 282: 349-354, 1970. [PubMed: 4188976] [Full Text: https://doi.org/10.1056/nejm197002122820701]
Alper, C. A., Abramson, N., Johnston, R. B., Jr., Jandl, J. H., Rosen, F. S. Studies in vivo and in vitro on an abnormality in the metabolism of C3 in a patient with increased susceptibility to infection. J. Clin. Invest. 49: 1975-1985, 1970. [PubMed: 4097977] [Full Text: https://doi.org/10.1172/JCI106417]
Alper, C. A., Rosen, F. S., Lachman, P. J. Inactivator of the third component of complement as an inhibitor in the properdin pathway. Proc. Nat. Acad. Sci. 69: 2910-2913, 1972. [PubMed: 4507613] [Full Text: https://doi.org/10.1073/pnas.69.10.2910]
Baracho, G. V., Nudelman, V., Isaac, L. Molecular characterization of homozygous hereditary factor I deficiency. Clin. Exp. Immun. 131: 280-286, 2003. [PubMed: 12562389] [Full Text: https://doi.org/10.1046/j.1365-2249.2003.02077.x]
Grumach, A. S., Leitao, M. F., Arruk, V. G., Kirschfink, M., Condino-Neto, A. Recurrent infections in partial complement factor I deficiency: evaluation of three generations of a Brazilian family. Clin. Exp. Immun. 143: 297-304, 2006. [PubMed: 16412054] [Full Text: https://doi.org/10.1111/j.1365-2249.2005.02988.x]
Sadallah, S., Gudat, F., Laissue, J. A., Spath, P. J., Schifferli, J.-A. Glomerulonephritis in a patient with complement factor I deficiency. Am. J. Kidney Dis. 33: 1153-1157, 1999. [PubMed: 10352206] [Full Text: https://doi.org/10.1016/S0272-6386(99)70155-1]
Servais, A., Fremeaux-Bacchi, V., Lequintrec, M., Salomon, R., Blouin, J., Knebelmann, B., Grunfeld, J.-P., Lesavre, P., Noel, L.-H., Fakhouri, F. Primary glomerulonephritis with isolated C3 deposits: a new entity which shares common genetic risk factors with haemolytic uremic syndrome. J. Med. Genet. 44: 193-199, 2007. [PubMed: 17018561] [Full Text: https://doi.org/10.1136/jmg.2006.045328]
Thompson, R. A., Lachmann, P. J. A second case of human C3b inhibitor (KAF) deficiency. Clin. Exp. Immun. 27: 23-29, 1977. [PubMed: 849647]
Vyse, T. J., Morley, B. J., Bartok, I., Theodoridis, E. L., Davies, K. A., Webster, A. D. B., Walport, M. J. The molecular basis of hereditary complement factor I deficiency. J. Clin. Invest. 97: 925-933, 1996. [PubMed: 8613545] [Full Text: https://doi.org/10.1172/JCI118515]
Vyse, T. J., Spath, P. J., Davies, K. A., Morley, B. J., Philippe, P., Athanassiou, P., Giles, C. M., Walport, M. J. Hereditary complement factor I deficiency. Quart. J. Med. 87: 385-401, 1994. [PubMed: 7922290]