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1/409. Missense mutations in the gp91-phox gene encoding cytochrome b558 in patients with cytochrome b positive and negative X-linked chronic granulomatous disease.

    Chronic granulomatous disease (CGD) is a disorder of host defense due to genetic defects of the superoxide (O2-) generating nadph oxidase in phagocytes. A membrane-bound cytochrome b558, a heterodimer consisting of gp91-phox and p22-phox, is a critical component of the oxidase. The X-linked form of the disease is due to defects in the gp91-phox gene. We report here biochemical and genetic analyses of patients with typical and atypical X-linked CGD. Immunoblots showed that neutrophils from one patient had small amounts of p22-phox and gp91-phox and a low level of O2- forming oxidase activity, in contrast to the complete absence of both subunits in two patients with typical CGD. Using polymerase chain reactions (PCR) on cDNA and genomic dna, we found novel missense mutations of gp91-phox in the two typical patients and a point mutation in the variant CGD, a characteristic common to two other patients with similar variant CGD reported previously. Spectrophotometric analysis of the neutrophils from the variant patient provided evidence for the presence of heme of cytochrome b558. Recently, we reported another variant CGD with similar amounts of both subunits, but without oxidase activity or the heme spectrum. A predicted mutation at amino acid 101 in gp91-phox was also confirmed in this variant CGD by PCR of the genomic dna. These results on four patients, including those with two variant CGD, are discussed with respect to the missense mutated sites and the heme binding ligands in gp91-phox. ( info)

2/409. Chronic granulomatous disease of childhood.

    Two boys and one girl suffering from recurrent severe bacterial infections were investigated. All 3 exhibited normal cellular and humoral immunity, normal neutrophil phagocytic ability, and defective neutrophil bacterial capacity. The clinical features and laboratory findings in these patients are diagnostic of chronic granulomatous disease. A sex-linked inheritance pattern was confirmed in 1 patient by the demonstration of a heterozygous carrier state in the mother. ( info)

3/409. Aspergillus osteomyelitis in a child who has p67-phox-deficient chronic granulomatous disease.

    Here we describe Aspergillus osteomyelitis of the tibia in a 9-year-old boy who has an autosomal recessive form of chronic granulomatous disease (CGD). The patient showed a p67-phagocyte oxidase (phox) deficiency, which is rare type of CGD in japan. The initial treatment which consisted of surgical debridement and antibiotic therapy with amphotericin b (AMPH), did not control the infection. aspergillus fumigatus (A. fumigatus) pure isolated from drainage fluid and necrotic bone tissue demonstrated less susceptible to antifungal agents, including AMPH, fluconazole and flucytosine. Recombinant interferon gamma was then administrated, and it was effective in controlling the course of severe invasive aspergillosis. This report indicates the use of interferon gamma might be helpful in control for Aspergillus osteomyelitis of the tibia in a child with CGD demonstrated p67-phox deficiency refractory to conventional therapy with AMPH. ( info)

4/409. A novel H( ) conductance in eosinophils: unique characteristics and absence in chronic granulomatous disease.

    Efficient mechanisms of H( ) ion extrusion are crucial for normal nadph oxidase function. However, whether the nadph oxidase-in analogy with mitochondrial cytochromes-has an inherent H( ) channel activity remains uncertain: electrophysiological studies did not find altered H( ) currents in cells from patients with chronic granulomatous disease (CGD), challenging earlier reports in intact cells. In this study, we describe the presence of two different types of H( ) currents in human eosinophils. The "classical" H( ) current had properties similar to previously described H( ) conductances and was present in CGD cells. In contrast, the "novel" type of H( ) current had not been described previously and displayed unique properties: (a) it was absent in cells from gp91- or p47-deficient CGD patients; (b) it was only observed under experimental conditions that allowed nadph oxidase activation; (c) because of its low threshold of voltage activation, it allowed proton influx and cytosolic acidification; (d) it activated faster and deactivated with slower and distinct kinetics than the classical H( ) currents; and (e) it was approximately 20-fold more sensitive to Zn(2 ) and was blocked by the histidine-reactive agent, diethylpyrocarbonate (DEPC). In summary, our results demonstrate that the nadph oxidase or a closely associated protein provides a novel type of H( ) conductance during phagocyte activation. The unique properties of this conductance suggest that its physiological function is not restricted to H( ) extrusion and repolarization, but might include depolarization, pH-dependent signal termination, and determination of the phagosomal pH set point. ( info)

5/409. A novel mutation in the CYBB gene resulting in an unexpected pattern of exon skipping and chronic granulomatous disease.

    Chronic granulomatous disease is a rare inherited disorder caused by non-existent or severely decreased phagocyte superoxide production that results in a severe defect in host defense and consequent predisposition to microbial infection. The enzyme responsible for superoxide production, nadph oxidase, involves at least five components. An absence of, or a defect in, any one of four of these proteins (p47(phox), p67(phox), p22(phox) and gp91(phox)) gives rise to the known types of chronic granulomatous disease. The most common form of inheritance is X-linked and is due to mutations in the CYBB gene that encodes gp91(phox), the large subunit of flavocytochrome b, the terminal electron donor of the oxidase. We have recently reported a large number of mutations in this gene revealing a broad range of defects, including large and small deletions, and frameshift, nonsense, missense, splice region and regulatory region mutations. Here we report a patient who has an unusual type of mutation that results in the generation of a 'pseudo-exon' in the gp91(phox) mRNA and an unexpected pattern of splicing. ( info)

6/409. Effectiveness of IFN-gamma for liver abscesses in chronic granulomatous disease.

    In chronic granulomatous disease, interferon-gamma (IFN-gamma) significantly reduces the incidence and severity of recurrent infections, but its effectiveness administered ex novo during acute infection has been reported in only one case. In this report, we describe two adult brothers with chronic granulomatous disease treated successfully with IFN-gamma for acute liver abscesses. Two brothers with severe recurrent infections of unknown origin were hospitalized for septic fever, malnutrition, and ultrasonographic evidence of liver abscess. Autosomal recessive chronic granulomatous disease was diagnosed based on lack of superoxide anion production by phagocytes and absence of p47-phox protein. An antibiotic regimen specifically directed against staphylococcus aureus was ineffective, whereas treatment with 50 microg/m2 IFN-gamma s.c. thrice weekly induced complete healing with scarring within 3 months. No septic recurrence was observed during a 4-year follow-up period. In chronic granulomatous disease, IFN-gamma is effective not only in preventing but also in healing life-threatening acute infections. ( info)

7/409. Donor lymphocyte infusion post-non-myeloablative allogeneic peripheral blood stem cell transplantation for chronic granulomatous disease.

    Chronic granulomatous disease (CGD) is a primary immunodeficiency disease symptomized by failure to generate superoxide and recurrent bacterial and fungal infections. Allogeneic bone marrow transplantation (BMT) is one of the therapeutic options available. However, it presents considerable risk to the recipient, especially if the patient is already at an advanced stage of disease, after repeated bacterial and fungal infections and organ damage. We present a case report of a 6-year-old child with long-standing CGD, severe clubbing, and jeopardized pulmonary function after multiple bacterial pulmonary infectious episodes, who had failed treatment with sulphamethazole trimethoprim, multiple antibiotic courses, itraconazole, as well as steroid and interferon-y therapy. He underwent allogeneic peripheral blood stem cell transplantation (alloPBSCT) from his HLA-matched MLC non-reactive sister following non-myeloablative conditioning. His ANC did not fall below 0.2 x 10(9)/l, his lowest WBC was 0.6 x 10(9)/l, and his platelets did not fall below 28 x 10(9)/l. He had normal engraftment, with no mucositis or organ toxicity. Neither parenteral nutrition nor platelet infusions were necessary. Partial donor chimerism following alloPBSCT was converted to full donor chimerism and superoxide production reverted to normal after donor lymphocyte infusions (DLI) from his HLA-matched sister. Twenty four months post transplant the patient is well, with stable and durable engraftment, 100% donor chimerism, normal superoxide production, no GVHD, and stabilization of his pulmonary condition. We suggest that alloPBSCT preceded by non-myeloablative conditioning and followed by DLI may constitute a successful mode of therapy for patients suffering from advanced CGD with recurrent infectious episodes resulting in organ dysfunction, enabling them to achieve full donor chimerism and normal superoxide production with minimal risk of transplant-related toxicity and GVHD. ( info)

8/409. bone marrow transplantation for chronic granulomatous disease: long-term follow-up and review of literature.

    Chronic granulomatous disease (CGD) is a heterogeneous group of disorders with defective respiratory burst activity in phagocytes which results in recurrent pyogenic infections. We report an 8-year-old boy with X-linked CGD who received an HLA-identical BMT from his sister. The nitroblue tetrazolium test returned to normal 3 months post transplant. Neutrophil engraftment has been stable for 7 years post BMT. Our patient was the eighth case of CGD successfully treated by BMT. Conditioning regimens in these patients have consisted mainly of BU and CY. We suggest that BMT is a safe and effective method of cure for patients with CGD. BMT should be considered for patients with HLA-identical siblings. ( info)

9/409. Molecular characterization of autosomal recessive chronic granulomatous disease caused by a defect of the nicotinamide adenine dinucleotide phosphate (reduced form) oxidase component p67-phox.

    Chronic granulomatous disease (CGD) is a rare inherited disorder of phagocytes in which defective production of microbicidal oxidants leads to severe recurrent infections. CGD is caused by mutations in any of 4 genes encoding components of nicotinamide adenine dinucleotide phosphate (reduced form; NADPH) oxidase, the multisubunit enzyme that produces the precursor of these oxidants, superoxide. Approximately 5% of CGD patients have an autosomal recessive form of disease caused by a severe deficiency of p67-phox, a 526-amino acid subunit of the oxidase that appears to regulate electron transport within the enzyme. Here we report the biochemical and molecular characterization of 6 unrelated kindreds with p67-phox deficiency. These studies show that, as in gp91-phox and p22-phox deficiencies, the p67-phox CGD patients show a high degree of heterogeneity in the genetic defects that underlie their disease. Five different mutant alleles were identified: (1) a nonsense mutation in exon 4 (C(304) --> T); (2) a 5-nucleotide (nt) deletion in exon 13 (nts 1169-1173); (3) a splice mutation in the first nucleotide of intron 4 (G --> A); (4) a deletion of 1 nt in exon 9 (A(728)); and (5) a 9-nt in-frame deletion in exon 2 (nts 55-63). The splice mutation was seen in 3 unrelated kindreds, while the 5-nt deletion was seen in 2 apparently unrelated families (both of Palestinian origin). Homozygosity was present in 4 of the kindreds, 2 of which had consanguineous parentage. In the isolated neutrophils of each of the affected patients in the 6 kindreds, there was no measurable respiratory burst activity and no p67-phox protein detected by immunoblot analysis. The level of 67-phox mRNA was less than 10% of normal in the mononuclear leukocytes from 3 of the 4 patients analyzed by Northern blot studies. Thus, this heterogeneous group of mutations in p67-phox all lead to marked instability of mRNA or protein (or both) that results in the complete loss of nadph oxidase activity. ( info)

10/409. nocardia farcinica pneumonia in chronic granulomatous disease.

    Infection with nocardia poses a diagnostic challenge in patients with chronic granulomatous disease (CGD) because the signs and symptoms are often nonspecific, delay in diagnosis is common, and invasive procedures are frequently required to obtain appropriate tissue specimens. We present the first reported case of N farcinica pneumonia in an adolescent with X-linked CGD. Differentiation of N farcinica from other members of N asteroides complex is important because of its propensity for causing disseminated infection and antimicrobial resistance. physicians caring for patients with CGD should maintain a high index of suspicion for nocardiosis, especially in those receiving chronic steroid therapy. early diagnosis remains critical for decreased morbidity and occasional mortality. ( info)
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