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Chronic granulomatous disease (CGD) is a diverse group of hereditary diseases in which certain cells of the immune system have difficulty forming the reactive oxygen compounds (most importantly, the superoxide radical) used to kill certain ingested pathogens.[1] This leads to the formation of granulomata in many organs.[2] CGD affects about 1 in 200,000 people in the United States, with about 20 new cases diagnosed each year.[3]
This condition was first described in 1957 as “a fatal granulomatosus of childhood”.[4][5] The underlying cellular mechanism that causes chronic granulomatous disease was discovered in 1967, and research since that time has further elucidated the molecular mechanisms underlying the disease.[6]
Phagocytes (i.e., neutrophils, monocytes, and macrophages) require an enzyme to produce reactive oxygen species to destroy bacteria after they ingest the bacteria in a process called phagocytosis. This enzyme is termed “phagocyte NADPH oxidase” (PHOX). The initial step in this process involves the one-electron reduction of molecular oxygen to produce superoxide anion, a free radical. Superoxide then undergoes a further series of reactions to produce products such as hydrogen peroxide, hydroxyl radical and hypochlorite (bleach). The reactive oxygen species this enzyme produces are toxic to bacteria and help the phagocyte kill them once they are ingested. Defects in one of the four essential subunits of this enzyme can all cause CGD of varying severity, dependent on the defect. There are over 410 known possible defects in the PHOX enzyme complex that can lead to chronic granulomatous disease[2].
Most cases of chronic granulomatous disease are transmitted as a mutation on the X chromosome and are thus called an “X-linked trait”.[7] The affected gene on the X chromosome codes for the gp91 protein p91-PHOX (p is the weight of the protein in kDa; the g means glycoprotein). CGD can also be transmitted in an autosomal recessive fashion (via CYBA and NCF1) and affects other PHOX proteins. The type of mutation that causes both types of CGD are varied and may be deletions, frame-shift, nonsense, and missense.[8][9]
A low level of NADPH, the cofactor required for superoxide synthesis, can lead to CGD. This has been reported in women who are homozygous for the genetic defect causing glucose-6-phosphate dehydrogenase deficiency (G6PD), which is characterised by reduced NADPH levels.
Classically, patients with chronic granulomatous disease will suffer from recurrent bouts of infection due to the decreased capacity of their immune system to fight off disease-causing organisms. The recurrent infections they acquire are specific and are, in decreasing order of frequency:
People with CGD are sometimes infected with organisms that usually do not cause disease in people with normal immune systems. Among the most common organisms that cause disease in CGD patients are the bacteria Staphylococcus aureus, Klebsiella species, and fungi such as Aspergillus species, and Candida species. Aspergillus has a propensity to cause infection in people with CGD and of the Aspergillus species, Aspergillus fumigatus seems to be most common in CGD.
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