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Chronic granulomatous disease ... (chronic granulomatous disease) - Genes CYBA, CYBB, NCF1, NCF2 and neutrophil cytosolic factor 4  

Chronic granulomatous disease is a disorder that causes a malfunction of the immune system, leading to a form of immunodeficiency. Individuals with chronic granulomatous disease have recurrent bacterial and fungal infections and often have granulomas in various tissues that can be harmful.

The characteristics of the disease usually appear in childhood, although some people do not show symptoms until later. In general, those affected have at least one serious bacterial infection or fungal every 3 to 4 years. The lungs are the most common area of infection. Individuals with chronic granulomatous disease are prone to pneumonitis, causing fever and respiratory distress after exposure to decomposing organic materials as manure, hay, or dead leaves. Exposure to these organic materials and numerous fungi involved in their decomposition makes people affected develop fungal infections in their lungs. Other common areas of infection in people affected include skin, liver and lymph nodes.

Inflammation can occur in many different areas of the body. More often, granulomas occur in the gastrointestinal tract and the genitourinary tract. In many cases, the intestinal wall becomes inflamed, causing a form of inflammatory bowel disease that can cause stomach pain, diarrhea, nausea and vomiting. Other common areas of inflammation include stomach, colon and rectum, and mouth and pharynx. Granulomas in the gastrointestinal tract can result in abscesses. Inflammation in the stomach can cause gastric outlet obstruction, which leads to inability to digest food. These digestive problems lead to vomiting after eating and weight loss. In the genitourinary tract, inflammation may occur in the kidneys, bladder and genitalia. Lymphadenitis and osteomyelitis, may result in further deterioration of the immune system. Rarely, affected people develop autoimmune disorders, such as myasthenia gravis and juvenile rheumatoid arthritis.

Chronic granulomatous disease is due to mutations in genes CYBA (cytochrome b-245 alpha chain), located on the long arm of chromosome 16 (16q24); CYBB (cytochrome b-245, beta polypeptide), located on the short arm of the X chromosome (Xp21.1); NCF1 (neutrophil cytosolic factor 1), located on the long arm of chromosome 7 (7q11.23); NCF2 (neutrophil cytosolic factor 2), located on the long arm of chromosome 1 (1q25), or neutrophil cytosolic factor 4 (neutrophil cytosolic factor 4), located on the long arm of chromosome 22 (22q13.1).

These genes encode proteins that form part of the enzyme NADPH oxidase, which plays an essential role in the immune system. Specifically, the complex acts primarily on phagocytes, which retain and destroy the phagocytosed microorganisms, such as bacteria and fungi. Inside phagocytes, NADPH oxidase complex is involved in the generation of superoxide anion, which is used to generate other toxic oxygen - derived elements that play a role in killing microorganisms phagocytosed. It is thought that NADPH oxidase also regulates the activity of neutrophils, that play a role in the balance of the inflammatory response to optimize healing and reduce injury in the body.

There are more than 40 mutations in the CYBA gene (responsible for less than 5% of cases of chronic granulomatous disease), more than 650 mutations in the CYBB gene (responsible for about 70%), several mutations in the gene NCF1 (responsible for about 25% of cases of chronic granulomatous disease), more than 50 mutations in the gene NCF2 (responsible for less than 5%) and at least two mutations in the (rare) neutrophil cytosolic factor 4 gene. Mutations leading to protein synthesis with reduced functionality, nonfunctional or absence of these. Without any of its protein subunits, the NADPH oxidase complex can not function properly. As a result, the phagocytes are unable to kill phagocytosed microorganisms and neutrophil activity is not regulated, resulting in a vulnerability to many types of infection and excessive inflammation. Some people do not have a mutation identified in any of these genes. The reason for the disease is unknown in these individuals.

When the disease is due to mutations in the CYBB gene is inherited in a recessive pattern X - linked, since the CYBB gene is on chromosome X. In males, an altered copy of the gene in each cell is sufficient to expressing the disease. In women, a mutation would have to happen in both copies of the gene for the disease to be expressed. Because it is unlikely that women have two altered copies of this gene, males are affected by X - linked recessive disorders much more frequently than women. A feature of the X - linked inheritance is that fathers can not pass X - linked traits to their sons chromosome. Rarely, women with an altered copy of the CYBB gene have mild symptoms of disease, such as increased frequency of bacterial or fungal infections. When the disease is caused by mutations in CYBA, NCF1, NCF2 or neutrophil cytosolic factor 4 gene is inherited in an autosomal recessive pattern, which means that both copies of the gene in every cell must have mutations for alteration is expressed. The parents of an individual with an autosomal recessive disease have a copy of the mutated gene, but usually show no signs and symptoms of the disease.

Tests in IVAMI: in IVAMI perform detection of mutations associated with chronic granulomatous disease, by complete PCR amplification of the exons of CYBA, CYBB, NCF1, NCF2 neutrophil cytosolic factor 4 and, respectively, genes and subsequent sequencing.

Samples recommended: EDTA blood collected for separation of blood leukocytes, or impregnated sample card with dried blood (IVAMI may mail the card to deposit the blood sample).