A single nucleotide deletion at the C1 inhibitor gene as the cause of hereditary angioedema: insights from a Brazilian family.

BACKGROUND: Hereditary angioedema is an autosomal dominant disease characterized by episodes of subcutaneous and submucosal edema. It is caused by deficiency of the C1 inhibitor protein, leading to elevated levels of bradykinin. More than 200 mutations in C1 inhibitor gene have been reported. The aim of this study was to analyze clinical features of a large family with an index case of hereditary angioedema and to determine the disease-causing mutation in this family. METHODS: Family pedigree was constructed with 275 individuals distributed in five generations. One hundred and sixty-five subjects were interviewed and investigated for mutation at the C1 inhibitor gene. Subjects reporting a history of recurrent episodes of angioedema and/or abdominal pain attacks underwent evaluation for hereditary angioedema. RESULTS: We have identified a novel mutation at the C1 inhibitor gene, c.351delC, which is a single-nucleotide deletion of a cytosine on exon 3, resulting in frameshift with premature stop codon. Sequencing analysis of the hypothetical truncated C1 inhibitor protein allowed us to conclude that, if transcription occurs, this protein has no biological activity. Twenty-eight members of the family fulfilled diagnostic criteria for hereditary angioedema and all of them presented the c.351delC mutation. Variation in clinical presentation and severity of disease was observed among these patients. One hundred and thirty-seven subjects without hereditary angioedema did not have the c.351delC mutation. CONCLUSION: The present study provides definitive evidence to link a novel genetic mutation to the development of hereditary angioedema in patients from a Brazilian family.

Proposal of abolition of the skin sensitivity test before equine rabies immune globulin application.

An epizootic outbreak of rabies occurred in 1995 in Ribeirão Preto, SP, with 58 cases of animal rabies (54 dogs, 3 cats and 1 bat) confirmed by the Pasteur Institute of São Paulo, and one human death. The need to provide care to a large number of people for the application of equine rabies immune globulin (ERIG) prevented the execution of the skin sensitivity test (SST) and often also the execution of desensitization, procedures routinely used up to that time at the Emergency Unit of the University Hospital of the Faculty of Medicine of Ribeirão Preto, University of São Paulo (EU-UHFMRP-USP), a reference hospital for the application of heterologous sera. In view of our positive experience of several years with the abolition of SST and of the use of premedication before the application of antivenom sera, we used a similar schedule for ERIG application. Of the 1489 victims of animal bites, 1054 (71%) received ERIG; no patient was submitted to SST and all received intravenously anti-histamines (anti-H1 + anti-H2) and corticosteroids before the procedure. The patients were kept under observation for 60 to 180 minutes and no adverse reaction was observed. On the basis of these results, since December 1995 ERIG application has been decentralized in Ribeirão Preto and has become the responsibility of the Emergency Unit of the University Hospital and the Central Basic Health Unit, where the same routine is used. Since then, 4216 patients have received ERIG (1818 at the Basic Health Unit and 2398 at the EU-UHFMRP), with no problems. The ideal would be the routine use of human rabies immune globulin (HRIG) in public health programs, but this is problematic, because of their high cost. However, while this does not occur, the use of SST is no longer justified at the time of application of ERIG, in view of the clinical evidence of low predictive value and low sensitivity of SST involving the application of heterologous sera. It is very important to point out that a negative SST result may lead the health team to a feeling of false safety that no adverse reaction will occur, but this is not true for the anaphylactoid reactions. The decision to use premedication, which is based on knowledge about anaphylaxis and on the pharmacology of the medication used, is left to the judgment of health professionals, who should always be prepared for eventual untoward events.

The treatment of allergic rhinitis improves the recovery from asthma and upper respiratory infections.

Forty-six asthmatic children with repeated respiratory infections presented symptoms of allergic rhinitis. All patients were treated locally for allergic rhinitis either with disodium cromoglycate or beclomethasone dipropionate. After six months of treatment, 95% of the children showed improvement of allergic rhinitis and 84% improvement of bronchial asthma, as well as fewer infections. We concluded that allergic rhinitis plays an important role in facilitating infections of the upper respiratory tract, and a possible association of rhinitis, viral infections and bronchial asthma is discussed.

Routine use of skin testing for immediate penicillin allergy to 6,764 patients in an outpatient clinic.

A population of 6,764 individuals who had received a penicillin prescription at an outpatient clinic was tested with MDM (minor determinant mixture) and PG (penicillin G), whether or not a previous history of allergy to penicillin had been reported. Ninety-six (1.4%) patients showed positive skin tests. The 6,668 patients with negative tests were treated with penicillin and none showed any immediate allergic reaction. Because of the large size of the sample it was possible to calculate that the probability of risk of systemic reactions among patients with negative tests who were immediately treated with penicillin was 1.5/million. The method used is simple to carry out and has proved to be safe and reliable for the identification or exclusion of immediate allergic reaction to penicillin.

Effects of Forssman antibody on renal function of the guinea pig.

When guinea pigs were injected with rabbit anti-sheep red blood cell antiserum (Forssman antibody) by the intra arterial (i.a.) route (abdominal aorta at the level of the renal arteries), they developed renal disfunction. A diminished glomerular filtration rate associated with a 27% increase in the fractional excretion of K+ was observed. No alterations were noted in the fractional excretion of water and NA+.

Nephropathy produced by Forssman antibody in guinea pigs: an experimental model of mesangial injury.

In the present work the involvement of the kidneys of guinea pigs injected with rabbit anti-sheep red blood cell antiserum (Forssman antibody) was studied. The antibody was introduced by a catheter into the abdominal aorta close to the openings of renal arteries. Glomerular lesions were observed 6 h following the injection: increased cellularity at the expense of polymorphonuclear and mononuclear cells, widened mesangial regions, deposits of fuchsinophilic material in the mesangium and capillary loops. By immunofluorescence the antibody was detected in the mesangial region extending to adjacent capillary loops, but it was not possible to demonstrate the presence of complement with certainty. The presence of subepithelial nodules on the glomerular basement membrane and deposits in the mesangium was demonstrated by electron microscopy. These findings suggest that this glomerulopathy induced by Forssman antibody may be a simple and reproducible model for the study of mesangial lesions.

Intravenous immunoglobulin (IVIG) attenuates antibody binding in acute haemorrhagic immunopneumonitis in a rat model of complement-dependent lung injury.

Administration of rabbit anti-rat lung serum (PNTS) to rats produces a fulminant haemorrhagic pneumonitis sensitive to the availability of complement. The present experiments were undertaken to assess whether a high dose of IVIG can affect the development of this kind of cytotoxic reaction. The experimental design included groups of Wistar rats pretreated intravenously with physiologic saline, IVIG or a preparation of human F(ab')2 fragments. One hour later the animals were challenged with either saline or PNTS. At 30 min after challenge, blood was collected and the lungs were removed. Pulmonary damage was evaluated by light microscopy; C3 deposits and the binding of immunoglobulins to the alveolar septa were assayed by immunofluorescence. The serum complement activity of the classical and alternative pathways was estimated by a kinetic technique. Pretreatment with IVIG decreased binding of rabbit anti-lung antibodies to alveolar septa and prevented the deposition of C3. These results indicate that pretreatment with IVIG inhibits the binding of the pathogenic antibody to lung tissue. Human IgG binding was not detected in any animal. The protection against lung injury afforded by pretreatment with IVIG, in contrast to the pneumotoxic effect of PNTS observed in control animals, was evident despite the administration of F(ab')2 to the rats. Since pretreatment with F(ab')2 failed to prevent the acute lung lesion, our results indicate that the attenuation afforded by IVIG in this model of complement-dependent tissue injury seems to be related to the integrity of the IgG molecule.