Complement Component 5 Deficiency

A number sign (#) is used with this entry because complement component 5 deficiency can be caused by homozygous or compound heterozygous mutation in the C5 gene (120900).

Clinical Features

Dysfunction of the fifth component of complement (C5) was found to be the basis for the deficiency in phagocytosis-enhancing activity of serum present in a proband, her mother, and 15 other relatives (Miller and Nilsson, 1970).

Jacobs and Miller (1972) reported a second family with deficiency of C5. However, in this family 2 brothers were affected and the laboratory characteristics of the deficiency were different. The presence of low opsonic indices in relatives through each parent supported autosomal recessive inheritance. The clinical picture of affected children in both families was that described by Leiner (1908). The 4 cardinal features are (1) generalized seborrheic dermatitis, (2) intractable diarrhea, (3) recurrent local and systemic infections, usually of gram-negative etiology, and (4) marked wasting. The diagnostic test is for uptake of particles (baker's yeast) by leukocytes, since C5 is required for full opsonization. Immunochemical assays of C5 are normal. Recognition of this disorder is important because effective therapy is available. Fresh plasma contains opsonically active C5, which is absent in 5-day-old stored bank blood. The pedigree of the first family, as presented by Miller et al. (1968), is probably as consistent with recessive inheritance as with dominant.

Rosenfeld and Leddy (1974) found a kindred with C5 deficiency through studies of a black woman with systemic lupus erythematosus, frequent bacterial infections, and absent serum hemolytic complement activity. A healthy half sister had almost no C5 and 4 relatives had about half normal levels. The ability of the proband's serum to promote phagocytosis of baker's yeast by normal or self neutrophils was unimpaired--an apparent conflict with other studies cited above. Asghar et al. (1991) described C5 deficiency in association with discoid lupus erythematosus.

Snyderman et al. (1979) demonstrated that repeated disseminated gonococcal infection can be associated with C5 deficiency. They excluded linkage with HLA-A and HLA-B, as did Rosenfeld et al. (1976).

Sanal et al. (1992) described a 3-generation consanguineous Turkish family in which many individuals had C5 deficiency. Affected individuals had recurrent meningitis and meningococcemia, as well as recurrent purulent otitis media. One 13-year-old male with demonstrated C5 deficiency had no increased susceptibility to infection.

Molecular Genetics

In affected members 2 African American families segregating C5 deficiency (609536), Wang et al. (1995) identified mutations in the C5 gene (120900.0001-120900.0002).

Population Genetics

By screening for complement deficiencies in 145,640 blood donors from Osaka and combining their results with reports of 92,686 donors from throughout Japan, Fukumori and Horiuchi (1998) identified 5 individuals with C5 deficiency, 6 individuals with C6 deficiency (612446), 17 individuals with C7 deficiency (610102), 5 individuals with C8 alpha/gamma deficiency (613790), and 439 individuals with C9 deficiency (613825).

Animal Model

Miller and Nilsson (1970) studied genetic deficiency of C5 in mice.

In mice with C5 deficiency, Wetsel et al. (1990) found a deletion of 2 basepairs, TA, near the 5-prime end of the C5 cDNA. The deletion shifted the reading frame with the creation of a termination codon, UGA, 4 basepairs downstream from the deletion. The same deletion was found in 6 C5-deficient strains but in none of 4 C5-sufficient strains.

History

Schifferli and Hirschel (1985) suggested that deficiency of a late component of complement (C5 to C8) was present in G. D. Heist of Philadelphia, a scientist who gave the first description of complement deficiency and who himself died of meningococcal meningitis. The paper of Heist et al. (1922) stated: 'The subsequent history of man 'H' illustrates the lack of resistance to meningococcal infection that accompanies absence of bactericidal power against the meningococcus. Man 'H' was no other than Dr. George D. Heist, the chief author of this paper. With no known contact with patient or carrier, in the absence of any known cases in the city, Dr. Heist in August, 1920, developed epidemic cerebrospinal meningitis, and although the diagnosis was made early, the patient succumbed--a loss beyond measure to science and to his friends. The unique interest attaching to the case suggests the publication of certain particulars. Dr. Heist was 36 years of age. His father had died at the age of 24 of typhoid fever, the course of which presented many points of similarity to the fatal illness of the son. Four paternal uncles had died of acute illnesses that were said to have 'gone to the head.'' The work reported by Heist et al. (1922) concerned bactericidal properties of whole blood against strains of meningococcus. Control blood without bactericidal activity came from Dr. Heist. Schifferli and Hirschel (1985) excluded deficiency of an early component of complement because of the absence of recurrent pyogenic infection or features of lupus. They excluded properdin deficiency, which can be accompanied by susceptibility to meningococcal meningitis, because of its X-linked inheritance (312060).

Leiner (1908) described 43 children with an illness of generalized erythroderma, diarrhea, and failure to thrive, developing at the end of the first or beginning of the second month of life. He named the disorder 'erythroderma desquamativa.' Simon et al. (1965) described 3 male sibs with erythroderma, severe diarrhea, and reduced resistance to infection. Death occurred at the age of 2, 6 and 9 months. Postmortem findings included lymphatic hypoplasia and increase in reticular cells of the lymph nodes. Since that time, the designation 'Leiner's disease' has been used for a heterogeneous group of disorders covering a spectrum of erythroderma including atopic eczema, infantile seborrheic dermatitis, ichthyosiform erythroderma (242100), Netherton disease (256500), and immunodeficiency syndromes. Glover et al. (1988) urged that the term 'Leiner's disease' be avoided. They described 2 sibs and 3 other unrelated children with various immunologic abnormalities. Shield et al. (1992) stated that one of the children was later known to have Netherton syndrome and another Omenn syndrome (603554).