Mutations in the X-linked and autosomal recessive forms of chronic granulomatous disease

Abstract

HRONIC granulomatous disease (CGD) is an immuno-C deficiency syndrome characterized clinically by severe recurrent bacterial and fungal infections that are difficult to treat by conventional means.These infections predominate in the lymph nodes, the subcutaneous tissues, the lungs, the liver and the bones.Gastrointestinal manifestations include diarrhea, perianal abscesses, and obstructions caused by granuloma formation.The disease is usually recognized in young children below the age of 2, but sometimes it is recognized later.'Biochemically, CGD is characterized by the inability of phagocytic leukocytes (neutrophils, eosinophils, monocytes, and macrophages) to generate reactive oxygen compounds, which are needed for intracellular killing of phagocytized microorganisms.'Therefore, the most common pathogens encountered in CGD patients are catalase-positive organisms, because catalase prevents the CGD phagocytes from using microbial-generated hydrogen peroxide for killing these pathogens.Predominant are Staphylococcus uureus, Aspergillus species, and a variety of Gram-negative enteric bacilli.CGD is a rare disease, with an estimated incidence of 1 in about 250,000 individuals, without any ethnic preference.Clinically and biochemically, CGD is a very heterogenous disorder due to the existence of many antimicrobial systems that can partially compensate for the defect in oxygen-dependent killing systems and to the complicated genetic origin of CGD.In this review, a short overview will be given of our present knowledge of the NADPH oxidase, the enzyme that is responsible for the production of antimicrobial oxygen compounds in leukocytes.This will be followed by a summary of all known mutations in the genes that encode the various NADPH oxidase components, and thus lead to the manifestation of CGD.This knowledge is of importance for a better understanding of the functional domains within the oxidase components, for improved prenatal and postnatal diagnosis of CGD, and for advances in therapy, including the future use of gene replacement.