Invasive meningococcal disease in three siblings with hereditary deficiency of the 8(th) component of complement: evidence for the importance of an early diagnosis

Abstract

Background: Deficiency of the eighth component of complement (C8) is a very rare primary immunodeficiency, associated with invasive, recurrent infections mainly caused by Neisseria species. We report functional and immunochemical C8 deficiency diagnosed in three Albanian siblings who presented with severe meningococcal infections at the age of 15 years, 4 years and 17 months, respectively. The youngest suffered serious complications (necrosis of fingers and toes requiring amputation).

Methods: Functional activity of the classical, alternative and mannose-binding lectin complement pathways was measured in serum from the 3 siblings and their parents (37-year-old woman and 42-year-old man). Forty healthy subjects (20 males and 20 females aged 4-38 years) served as normal controls. Serum complement factors were measured by haemolytic assays and immunoblotting. Sequence DNA analysis of the C8B gene was performed.

Results: Analyses of the three complement pathways revealed no haemolytic activity and also absence of C8beta in serum samples from all three siblings. The genetic analysis showed that the three siblings were homozygous for the p.Arg428* mutation in the C8B gene on chromosome 1p32 (MIM 120960). The parents were heterozygous for the mutation and presented normal complement activities. A 2-year follow-up revealed no further infective episodes in the siblings after antibiotic prophylaxis and meningococcal vaccination.

Conclusions: Complement deficiencies are rare and their occurrence is often underestimated. In presence of invasive meningococcal infection, we highlight the importance of complement screening in patients and their relatives in order to discover any genetic defects which would render necessary prophylaxis to prevent recurrent infections and severe complications.

Keywords: C8 deficiency; Complement deficiency; Meningococcal disease; Neisseria meningitidis.

Fig. 1

Upper panel. Levels of C8 antigen in serum from the three patients and their parents as well as in normal human serum (NHS). Lower panel. Sodium Dodecyl Sulphate-PolyAcrylamide Gel Electrophoresis (SDS-PAGE) and immunoblotting analysis of C8 in serum from the three patients and their parents as well as in NHS. The last lane on the right refers to molecular markers of known molecular weight

Fig. 2

a Pedigree of the family. Filled symbols indicate affected individuals. The genotype for each family member is reported: +/− indicated the heterozygous and −/− the homozygous for the mutant allele. b Direct fluorescent sequencing of the exon 9 of the C8B gene. A control sequence homozygous for p.248Arg is reported along with the sequences from a heterozygous parent and a sib homozygous for the p.248Stop