Chapter 13 - Chronic Granulomatous Disease – from a Fatal Disease to a Curable One

Abstract

In 1957, a “new syndrome” of recurrent infections was recognized and named “fatal granulomatous disease of childhood”. It took ten more years to figure out that neutrophils from these patients (now described as having chronic granulomatous disease [CGD]), were able to digest but not kill staphylococci and other microorganisms. This discovery led to the recognition that CGD neutrophils were endowed with reduced oxidative activity due to a defect in NADPH oxidase, which was recognized as a multicomponent enzyme required for neutrophil killing. By 1990, all proteins (and their genes) that created this enzyme complex were identified as membrane bound (cytochrome b558, comprised of gp91phox and p22phox) and cytosolic (p47phox, p67phox and p40phox) components. Sorting out the molecular basis of X-linked and autosomal recessive CGD not only facilitated diagnosis, but allowed genotype/phenotype correlation, and contributed to selection of optimal therapies, including antimicrobial prophylaxis, interferon-γ, hematopoietic stem cell transplantation and gene therapy.