Chronic granulomatous disease with partial deficiency of cytochrome b558 and incomplete respiratory burst: variants of the X-linked, cytochrome b558-negative form of the disease

Abstract

Five male patients from four different families presented with a clinical record of chronic granulomatous disease (CGD): recurrent infections of the skin and/or respiratory tract with catalase-positive microorganisms, sometimes in combination with granulomata and/or abscesses in various organs. These patients differed from "classical" forms of the disease in that their neutrophils, although deficient in killing in vitro of Staphylococcus aureus, contained a decreased but measurable amount of cytochrome b558 (10-60% of normal on a heme basis), causing weak staining in the nitroblue tetrazolium dye test and a depressed respiratory burst after contact of the cells with fluid or particulate activators of the NADPH:O2 oxidoreductase. In the cell-free activation system, the defect in the patients' cells was localized in the membrane fraction. In each of the four families, the cellular abnormalities showed an X-linked inheritance. Fusion experiments performed with the monocytes from these patients and those from patients with classical X-linked, cytochrome b558-negative (Xb(0)) or autosomal, cytochrome b558-positive (Ab+) CGD showed complementation of NADPH:O2 oxidoreductase activity in the latter but not in the former combination. Thus, the unusual CGD patients represent variant forms of Xb(0) CGD, with mutations in the gene coding for the beta subunit of cytochrome b558 that do not cause complete loss of this protein.

Diffuse interstitial pneumonia and pulmonary hypertension: a novel manifestation of chronic granulomatous disease

“…Of X-linked CGD cases, ,10% have a reduced gp91phox protein level with measurable amounts of ROS [9,10]. This residual activity could explain the lack of severe infection in the present patient, since it appears that having even a small proportion of phagocytes that are NADPH-positive can reduce the risk of serious infection [2,11,12].…”

Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease

“…Observations of female carriers of X-linked CGD (X-CGD), who have a dimorphic population of both normal and oxidase-negative neutrophils, suggest that full restoration or respiratory burst activity to approximately 10% of circulating neutrophils could ameliorate the clinical manifestations of CGD. 10,[18][19][20] "Variant" patients with X-CGD with small amounts of residual NADPH oxidase activity (2% to 10% of normal) often have a milder clinical course, [21][22][23][24] although some still develop significant infectious or granulomatous complications. 21,[25][26][27][28] Hence, only partial correction of superoxide generation may be insufficient to restore full microbicidal function to phagocytes.…”

“…10,[18][19][20] "Variant" patients with X-CGD with small amounts of residual NADPH oxidase activity (2% to 10% of normal) often have a milder clinical course, [21][22][23][24] although some still develop significant infectious or granulomatous complications. 21,[25][26][27][28] Hence, only partial correction of superoxide generation may be insufficient to restore full microbicidal function to phagocytes. It is unknown how incomplete correction of superoxide-generating activity, as might occur if vector-driven expression of the missing phox subunit is less than normal, might influence the clinical benefit of HSC-targeted gene therapy when only a minority of phagocytes is corrected.…”

A point mutation in gp91-phox of cytochrome b558 of the human NADPH oxidase leading to defective translocation of the cytosolic proteins p47-phox and p67-phox.

“…Virtually all patients with cytochrome b defects lack gp9 1-phox and p22-phox, regardless ofwhich gene is affected by the mutation (1 1, 12, 13). Complete absence of both subunits in X-linked CGD is referred to as X9 10, whereas a residual amount of cytochrome is designated X91- (14). Sofar, only two X-linked CGD patients have been described as X9 1 , with (almost) normal amounts ofcytochrome b558 present in their neutrophils ( 15,16).…”