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Chronic granulomatous disease
Classification and external resources
Superoxide
ICD-10D71.
ICD-9758.0
OMIM306400 233690 233700
DiseasesDB2633
MedlinePlus001239
eMedicineped/1590  derm/719
MeSHD006105

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. Superoxide is the Anion O2&minus It is important as the product of the one-electron reduction of Dioxygen, which occurs widely in nature The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The International Statistical Classification of Diseases and Related Health Problems 10th Revision ( ICD -10) is a coding of diseases and signs symptoms abnormal findings The International Statistical Classification of Diseases and Related Health Problems (most commonly known by the abbreviation ICD) provides codes to classify Diseases The following is a list of codes for International Statistical Classification of Diseases and Related Health Problems. The Mendelian Inheritance in Man project is a Database that catalogues all the known Diseases with a genetic component, and—when possible—links them The Diseases Database is a free Website that provides information about the relationships between medical conditions Symptoms, and Medications. MedlinePlus, with the MedlinePlus Medical Encyclopedia, is a website network containing Health information from the world's largest medical Library eMedicine is an online clinical medical knowledge base that was founded in 1996 by Scott Plantz and Richard Lavely two medical doctors Medical Subject Headings ( MeSH) is a huge Controlled vocabulary (or metadata system for the purpose of indexing journal articles and books A genetic disorder is a condition caused by abnormalities in Genes or Chromosomes While some diseases such as Cancer, are due to genetic abnormalities acquired An immune system is a collection of mechanisms within an Organism that protects against Disease by identifying and killing Pathogens and Tumor Oxygen (from the Greek roots ὀξύς (oxys (acid literally "sharp" from the taste of acids and -γενής (-genēs (producer literally begetteris the Superoxide is the Anion O2&minus It is important as the product of the one-electron reduction of Dioxygen, which occurs widely in nature A pathogen (from Greek πάθος pathos "suffering passion" and γἰγνομαι (γεν- gignomai (gen- "I give birth to" infectious [1] This leads to the formation of granulomata in many organs. In Medicine ( Anatomical pathology) a granuloma (classical Latin plural granulomata; modern anglicized plural granulomas, also accepted [2] CGD affects about 1 in 200,000 people in the United States, with at least 20 new cases diagnosed each year. The United States of America —commonly referred to as the [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]

Contents

Pathophysiology

Two neutrophils among many red blood cells. Neutrophils are one type of cell affected by chronic granulomatous disease.
Two neutrophils among many red blood cells. Neutrophil granulocytes, generally referred to as neutrophils, are the most abundant type of White blood cells in humans and form an essential part of the Red blood cells are the most common type of Blood cell and the Vertebrate body's principal means of delivering Oxygen to the body tissues via the Blood Neutrophils are one type of cell affected by chronic granulomatous disease.

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. Neutrophil granulocytes, generally referred to as neutrophils, are the most abundant type of White blood cells in humans and form an essential part of the Monocyte is a type of Leukocyte, part of the Human body 's Immune system. Macrophages ( Greek: "big eaters" from makros "large" + phagein "eat" ( Mø) are cells within the tissues that Enzymes are Biomolecules that catalyze ( ie increase the rates of Chemical reactions Almost all enzymes are Proteins Reactive oxygen species (ROS are ions or very small molecules that include Oxygen Ions free radicals, and Peroxides both inorganic and The Bacteria ( singular: bacterium) are a large group of unicellular Microorganisms Typically a few Micrometres in length bacteria have Phagocytosis is the cellular process of engulfing solid particles by the Cell membrane to form an internal Phagosome, or "food vacuole 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 free radical. Superoxide is the Anion O2&minus It is important as the product of the one-electron reduction of Dioxygen, which occurs widely in nature Superoxide then undergoes a further series of reactions to produce products such as peroxide, hydroxyl radical and hypochlorite. The reactive oxygen species this enzyme produces are toxic to bacteria and help the phagocyte kill them once they are ingested. Reactive oxygen species (ROS are ions or very small molecules that include Oxygen Ions free radicals, and Peroxides both inorganic and 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].

Genetics

Most cases of chronic granulomatous disease are transmitted as a mutation on the X chromosome and are thus called an "X-linked trait". The X chromosome is one of the two sex-determining Chromosomes in many animal species including mammals (the other is the Y chromosome) [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). Proteins are large Organic compounds made of Amino acids arranged in a linear chain and joined together by Peptide bonds between the Carboxyl Cytochrome b-245 beta polypeptide (chronic granulomatous disease, also known as CYBB and P91-PHOX, is a human Gene encoding a Glycoprotein The unified atomic mass unit ( u) or Dalton ( Da) or sometimes universal mass unit, is an unit of Mass used to express Not to be confused with Peptidoglycan. Glycoproteins are proteins that contain Oligosaccharide chains ( Glycans) covalently attached CGD can also be transmitted in an autosomal recessive fashion (via CYBA and NCF1) and affects other PHOX proteins. Cytochrome b-245 alpha polypeptide, also known as CYBA, is a human Gene. Neutrophil cytosolic factor 1 (chronic granulomatous disease autosomal 1, also known as NCF1, is a human Gene. 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. Zygosity refers to the genetic condition of a Zygote. In genetics zygosity describes the similarity or dissimilarity of DNA between Homologous Glucose-6-phosphate dehydrogenase deficiency is an X-linked recessive Hereditary disease characterised by abnormally low levels of Glucose-6-phosphate

Clinical manifestations

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:

Microscopic image of the fungus, Aspergillus fumigatus, an organism that commonly causes disease in people with chronic granulomatous disease.
Microscopic image of the fungus, Aspergillus fumigatus, an organism that commonly causes disease in people with chronic granulomatous disease. Pneumonia is an inflammatory illness of the Lung. Frequently it is described as lung Parenchyma / alveolar inflammation and abnormal An abscess (abscessus is a collection of Pus (dead Neutrophils) that has accumulated in a cavity formed by the tissue on the basis of an infectious process Septic arthritis is the invasion of a Joint by an Infectious agent which produces Arthritis. Osteomyelitis is an Infection of Bone or Bone marrow, usually caused by Pyogenic Bacteria or Mycobacteria. Bacteremia ( Bacteræmia in British English is the presence of bacteria in the Blood. Fungemia (also known as Candidemia, Candedemia, and Invasive Candidiasis) is the presence of fungi or Yeasts in the Blood Cellulitis is an Infection of the deep Subcutaneous tissue of the Skin. Impetigo (sometimes impetaigo) is a superficial Bacterial Skin Infection most common among children 2 to 6 years old Aspergillus fumigatus is a Fungus of the Genus Aspergillus, and is one of the most common Aspergillus species to cause disease in

People with CGD are sometimes infected with unique organisms that usually do not cause disease in people with normal immune systems. Some of the organisms that cause disease in CGD patients are Staphylococcus aureus, Escheria coli, Klebsiella species, Aspergillus species, and Candida species. Staphylococcus aureus (ˌstæfɨləˈkɒkəs ˈɔriəs literally "Golden Cluster Seed" and also known as golden staph) is the most common cause of Klebsiella is a Genus of non-motile, Gram-negative, Oxidase-negative Bacteria with a prominent Polysaccharide Aspergillus is a Genus of around 200 Molds found throughout much of nature worldwide Candida is a Genus of Yeasts Many species of this genus are Endosymbionts

Aspergillus has a unique propensity to cause infection in people with CGD. Of the Aspergillus species, Aspergillus fumigatus seems to be the one that most commonly causes disease. Aspergillus fumigatus is a Fungus of the Genus Aspergillus, and is one of the most common Aspergillus species to cause disease in

Most people with CGD are diagnosed in childhood, usually before age 5. [7] Early diagnosis is important since these people can be placed on antibiotics to ward off infections before they occur.

Laboratory findings

The nitroblue-tetrazolium (NBT) test is the original and most widely-known test for chronic granulomatous disease. Nitro blue tetrazolium is a Chemical compound composed of two Tetrazole moieties. [10] It is negative in CGD, and positive in normal individuals. This test depends upon the direct reduction of NBT by superoxide free radical to form an insoluble formazan. Superoxide is the Anion O2&minus It is important as the product of the one-electron reduction of Dioxygen, which occurs widely in nature This test is simple to perform and gives rapid results, but only tells whether or not there is a problem with the PHOX enzymes, not how much they are affected. An advanced test called the cytochrome C reduction assay tells physicians how much superoxide a patient's phagocytes can produce. Once the diagnosis of CGD is established, a genetic analysis may be used to determine exactly which mutation is the underlying cause.

Treatment

Management of chronic granulomatous disease revolves around two goals: 1) diagnose the disease early so that antibiotics can be given to keep an infection from occurring, and 2) educate the patient about his or her condition so that prompt treatment can be given if an infection occurs. In modern usage an antibiotic is a Chemotherapeutic agent with activity against Microorganisms such as Bacteria, fungi or Protozoa

Physicians often prescribe the antibiotic trimethoprim-sulfamethoxazole to prevent bacterial infections. Co-trimoxazole (abbreviated SXT TMP-SMX TMP-SMZ or TMP-sulfa is an Sulphonamide, Antibacterial combination of Trimethoprim and Sulfamethoxazole [11] This drug also has the benefit of sparing the normal bacteria of the digestive tract. Fungal infection is commonly prevented with itraconazole,[12] although a newer drug of the same type called voriconazole may be more effective. Itraconazole (marketed as Sporanox by Janssen Pharmaceutica) invented in 1984 is a Triazole Antifungal agent that is prescribed to patients Voriconazole (VFEND Pfizer) is a Triazole Antifungal Medication that is generally used to treat serious invasive fungal [13] The use of this drug for this purpose is still under scientific investigation.

Interferon, in the form of interferon gamma-1b (Actimmune) is approved by the Food and Drug Administration for the prevention of infection in CGD. Interferons ( IFN s are natural Proteins produced by the cells of the Immune system of most Vertebrates in response to challenges by foreign agents Interferon-gamma ( IFN-γ) is a Dimerized soluble Cytokine that is the only member of the type II class of Interferons This interferon was originally It has been shown to prevent infections in CGD patients by 70% and to reduce their severity. Although its exact mechanism is still not entirely understood, it has the ability to give CGD patients more immune function and therefore, greater ability to fight off infections. This therapy has been standard treatment for CGD for several years. [14]

Gene therapy is currently being studied as a possible treatment for chronic granulomatous disease. CGD is well-suited for gene therapy since it is caused by a mutation in single gene which only affects one body system (the hematopoietic system). Haematopoiesis (from Ancient Greek haima blood poiesis to make (or hematopoiesis in the United States sometimes also haemopoiesis or Viruses have been used to deliver a normal gp91 gene to rats with a mutation in this gene, and subsequently the phagocytes in these rats were able to produce oxygen radicals. In Chemistry, radicals (often referred to as free radicals) are atoms molecules or ions with Unpaired electrons on an otherwise Open shell [15]

In 2006, two human patients with X-linked chronic granulomatous disease underwent gene therapy and blood cell precursor stem cell transplantation to their bone marrow. Stem cells are cells found in most if not all multi-cellular Organisms. Bone marrow is the flexible tissue found in the hollow interior of Bones In adults marrow in large bones produces new Blood cells It constitutes 4% of Both patients recovered from their CGD, clearing pre-existing infections and demonstrating increased oxidase activity in their neutrophils. However, long-term complications of this therapy are unknown. [16]

Prognosis

The prognosis of chronic granulomatous disease is guarded, with long-term outcomes closely tied to early diagnosis and early therapeutic intervention. With increasing treatment options for CGD the life-span for these patients is expected to also increase.

References

  1. ^ Chronic Granulomatous Disease: Immunodeficiency Disorders: Merck Manual Professional. Retrieved on 2008-03-01. 2008 ( MMVIII) is the current year in accordance with the Gregorian calendar, a Leap year that started on Tuesday of the Common Events 86 BC - Lucius Cornelius Sulla, at the head of a Roman Republic army enters in Athens, removing the Tyrant
  2. ^ a b Heyworth P, Cross A, Curnutte J (2003). "Chronic granulomatous disease. ". Curr Opin Immunol 15 (5): 578-84. doi:10.1016/S0952-7915(03)00109-2. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 14499268.  
  3. ^ Maryland Pao, M. D. et al. (2004). "Cognitive Function in Patients With Chronic Granulomatous Disease: A Preliminary Report". Psychosomatics 45 (June 2004): 230-4. PMID 15123849.  
  4. ^ Berendes H, Bridges RA, Good RA (1957). "A fatal granulomatosus of childhood: the clinical study of a new syndrome". Minn Med 40 (5): 309-12. PMID 13430573.  
  5. ^ Bridges RA, Berendes H, Good RA (1959). "A fatal granulomatous disease of childhood; the clinical, pathological, and laboratory features of a new syndrome". AMA J Dis Child 97 (4): 387-408. PMID 13636694.  
  6. ^ Baehner RL, Nathan DG (1967). "Leukocyte oxidase: defective activity in chronic granulomatous disease". Science 155 (764): 835-6. doi:10.1126/science.155.3764.835. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 6018195.  
  7. ^ a b Winkelstein J, Marino M, Johnston R et al (2000). "Chronic granulomatous disease. Report on a national registry of 368 patients. ". Medicine (Baltimore) 79 (3): 155-69. PMID 10844935.  
  8. ^ Heyworth P, Curnutte J, Rae J, Noack D, Roos D, van Koppen E, Cross A (2001). "Hematologically important mutations: X-linked chronic granulomatous disease (second update). ". Blood Cells Mol Dis 27 (1): 16-26. doi:10.1006/bcmd.2000.0347. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 11162142.  
  9. ^ Cross A, Noack D, Rae J, Curnutte J, Heyworth P (2000). "Hematologically important mutations: the autosomal recessive forms of chronic granulomatous disease (first update). ". Blood Cells Mol Dis 26 (5): 561-5. doi:10.1006/bcmd.2000.0333. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 11112388.  
  10. ^ Kasper, DL, Fauci, AS, Longo, DL, Braunwald, E, Hauser, SL, and Jameson, JL. Harrison's Principles of Internal Medicine, 16th edition 2005;357. ISBN 0-07-139140-1.
  11. ^ Weening R, Kabel P, Pijman P, Roos D (1983). "Continuous therapy with sulfamethoxazole-trimethoprim in patients with chronic granulomatous disease. ". J Pediatr 103 (1): 127-30. PMID 6408232.  
  12. ^ Cale C, Jones A, Goldblatt D (2000). "Follow up of patients with chronic granulomatous disease diagnosed since 1990. ". Clin Exp Immunol 120 (2): 351-5. doi:10.1046/j.1365-2249.2000.01234.x. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 10792387.  
  13. ^ Sabo J, Abdel-Rahman S (2000). "Voriconazole: a new triazole antifungal. ". Ann Pharmacother 34 (9): 1032-43. doi:10.1345/aph.19237. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 10981251.  
  14. ^ "A controlled trial of interferon gamma to prevent infection in chronic granulomatous disease. The International Chronic Granulomatous Disease Cooperative Study Group. " (1991). N Engl J Med 324 (8): 509-16. PMID 1846940.  
  15. ^ Dinauer M, Gifford M, Pech N, Li L, Emshwiller P (2001). "Variable correction of host defense following gene transfer and bone marrow transplantation in murine X-linked chronic granulomatous disease. ". Blood 97 (12): 3738-45. doi:10.1182/blood.V97.12.3738. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 11389011.  
  16. ^ Ott M, Schmidt M, Schwarzwaelder K, et al. (2006). "Correction of X-linked chronic granulomatous disease by gene therapy, augmented by insertional activation of MDS1-EVI1, PRDM16 or SETBP1. ". Nat Med 12 (4): 401-9. doi:10.1038/nm1393. A digital object identifier ( DOI) is a permanent identifier given to an Electronic document. PMID 16582916.  

External links

Dictionary

chronic granulomatous disease

-noun

  1. (medicine) Any of a group of hereditary defects in the ability of some phagocytes to kill certain bacteria; the resulting infection
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