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In medicine (genetics and pediatrics) chronic granulomatous disease (CGD) is a hereditary disease where neutrophil granulocytes are unable to destroy ingested pathogens. It leads to the formation of granulomata in many organsHeyworth PG, Cross AR, Curnutte JT. Chronic granulomatous disease. Curr Opin Immunol 2003;15:578–584. PMID 14499268..
Pathophysiology
Neutrophils require a set of enzymes to produce reactive oxygen species to destroy bacteria after their phagocytosis. Together these enzymes are termed "phagocyte NADPH oxidase" (phox). Defects in one of these enzymes can all cause CGD of varying severity, dependent on the defect. There are over 410 known defects in the enzyme complex.
Genetics
Four genes have been implicated in CGD (p is the weight of the protein in kDa; the g means glycoprotein):
- CYBB, coding the gp91-phox subunit (X-linked, accounts for 2/3 of the cases);
- CYBA, coding p22-phox
- NCF-1, coding p47-phox
- NCF-2, coding p67-phox
- A fifth gene, coding for p40-phox, has not been implicated
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.
Epidemiology
This rare disease occurs in about 1 on 200,000 - 250,000 live births.
Treatment
Infections are prevented by prophylactic antibiotics, usually in the form of co-trimoxazole as it spares the normal bacteria of the digestive tract. Interferon, in the form of interferon gamma-1b (Actimmune®) prevents infections by 70% and reduces their severity, and has been standard treatment for CGD for several yearsA controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group. N Engl J Med 1991;324:509-16. PMID 1846940.
A 2006 studyOtt MG, Schmidt M, Schwarzwaelder K, Stein S, Siler U, Koehl U, Glimm H, Kuhlcke K, Schilz A, Kunkel H, Naundorf S, Brinkmann A, Deichmann A, Fischer M, Ball C, Pilz I, Dunbar C, Du Y, Jenkins NA, Copeland NG, Luthi U, Hassan M, Thrasher AJ, Hoelzer D, von Kalle C, Seger R, Grez M. Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. Nat Med 2006;12:401-9. PMID 16582916. suggested that gene therapy had been successful in two cases (men ages 16 and 25). One has since died in April 2006 Abbott A. Scientists investigate gene-therapy death. http://www.nature.com/news/2006/060424/pf/060424-14_pf.html
References
"Chronic granulomatous disease"