Page 1 of 2: Microbiology: chronic granulaomatous disease

cingulate_gyrus2006 · Credits: 22760 My Scrapbook

this is an AIIMS Nov 2004 ques.
Which one of the following statements is correct regarding chronic granulaomatous disease-
a) It is an autosomal dominant disease.
b) It is characterized by abnormal bacterial phagocytosis.
c) Recurrent streptococcal infections are usual in this disease
d) Nitroblue tetrazolium test is useful for screening.

drsmita_s · Credits: 18609 My Scrapbook

answer is option d) Nitroblue tetrazolium test is useful for screening

inheritance in chronic granulaomatous disease is autosomal recessive or x linked.
there is a defect in H2O2 production , so phagocytosis will occur normally ,but bacteria will not be killed .
catalase producing organisms will not be killed since they will destroy whatever little H2O2 is left in the cell , but catalase negative organisms like strep and pneumococcus will be handled normally .
option d is correct.

nabrina · Credits: 3146 My Scrapbook

Ya the fault lies in the NADPH oxidase system . nothing to do with phagocytosis .clinical manifestations of CGD arise from mutations → loss / functional inactivation of components of the NADPH oxidase
FYI → The phagocyte NADPH oxidase (designated "PHOX") consists of five subunits:
• Two subunits, gp91(PHOX) and p22(PHOX), form the heavy and light chains of the cytochrome b558 (CYBB) heterodimeric flavohemoprotein, → located in the membranes of secretory vesicles and granules.
• The remaining three subunits, (p40(PHOX), p47(PHOX), and p67(PHOX)), exist as a cytosolic complex.
In normal course of the matter Phagocytosis of micro-organisms → Stimulus for phagocyte activation → cytosolic complex of the NADPH oxidase System → migrates to the cell membrane, associates with the cytochrome b558 complex, and in the presence of NADPH is able to generate superoxide from oxygen

Types of CGD as per components involved
• M/C form (70%)→ mutations in the gene encoding gp91 → located on the X-chromosome → explains XLR inheritance
• remaining cases (~ 30 %) → mutations in the autosomally encoded p22(PHOX), p47(PHOX), and p67(PHOX) subunits → autosomal recessive

cingulate_gyrus2006 · Credits: 22760 My Scrapbook

Yes Answer is C

CHRONIC GRANULOMATOUS DISEASE
Chronic granulomatous disease (CGD) is characterized by the ability of neutrophils and monocytes to ingest but their inability to kill catalase-positive microorganisms because of a defect in the generation of microbial oxygen metabolites,caused by genes affecting one X-linked and three autosomal recessive chromosomes.
Genetics and Pathogenesis.
Approximately two thirds of patients with CGD are males who inherit their disorder as a result of mutations in the X-chromosome gene encoding gp91phox .
About one third of patients inherit CGD in an autosomal recessive fashion resulting from mutations in the gene encoding p47phox on chromosome 7.
Defects in the genes encoding p67phox (chromosome 1) or p22phox (chromosome 16) also occur; these are inherited in an autosomal recessive manner and account for about 5% of cases of CGD.

Laboratory Findings.
For screening of CGD, the nitroblue tetrazolium (NBT) dye test is still widely used,
but it is rapidly being replaced by the more accurate flow cytometry test using dihydrorhodamine 123 fluorescence (DHR test). DHR detects oxidant production because it increases fluorescence when oxidized by H2 O2 .

Nelson Page 715 , 17 th edition.

cingulate_gyrus2006 · Credits: 22760 My Scrapbook

Some additional points I got from Net.

Enzyme in volved in CGD is termed "phagocyte NADPH oxidase" (PHOX).
The phox system is an NADPH oxidase enzyme complex consisting of 5 component proteins. Glycoprotein 91 (gp91) and protein 22 (p22) make up the b and a subunits of a membrane bound heterodimer referred to as flavocytochrome b558.
Protein 47 (p47), protein (p67), and protein 40 (p40) exist together as the cytosolic components of phox. The membrane-bound (gp91 and p22) and cytosolic components (p47, p67, and p40) assemble at the phagolysosome membrane in response to inflammatory stimuli such as phagocytosis.

The most common molecular defect in CGD is a mutation in the CYBB (cytochrome B, b subunit) gene that is located on the X chromosome and that encodes for gp91 (the b subunit of cytochrome b558). The resulting syndrome is commonly called X-linked CGD (X-CGD). Gp91 deficiency accounts for 50-70% of all cases of CGD.
he initial step in this process involves the one-electron reduction of molecular oxygen to produce Superoxide free radical. 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. 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[1].
Catalase + organism cause infections in CGD.But. Both Pseudomonas aeruginosa and Burkholderia cepacia (also known as Pseudomonas cepacia) are catalase-positive organisms, the former is a rare pathogen in CGD.
because CGD neutrophils can kill P aeruginosa organisms by means of nonoxidative mechanisms. B cepacia is an important cause of infections in CGD perhaps because of as-yet unexplained abilities to resist killing in neutrophil-mediated nonoxidative pathways.

The nitroblue-tetrazolium (NBT) test is the original and most widely-known test for chronic granulomatous disease. It is negative in CGD, and positive in normal individuals.

cingulate_gyrus2006 · Credits: 22760 My Scrapbook

Other disorders of Phagocyte Function are

LEUKOCYTE ADHESION DEFICIENCY
CHÉDIAK-HIGASHI SYNDROME
MYELOPEROXIDASE DEFICIENCY

aap · Credits: 2286 My Scrapbook

the ans is d. ref textbook of immunolgy kuby and ananthnarayan

drsmita_s · Credits: 18609 My Scrapbook

nabrina · Credits: 3146 My Scrapbook

But NBT is not that specific

Increased In

Bacterial infections, including miliary TB and TB meningitis
Nocardia and other systemic fungal infections
Various parasitic infections (e.g., malaria)
Chediak-Higashi syndrome
Idiopathic myelofibrosis
Normal infants up to age 2 months
Pregnancy
Patients taking birth control pills
Some patients with lymphoma suppressed by chemotherapy

Decreased or Normal In Absence of Bacterial Infection
Chronic granulomatous disease
Normal persons
Postpartum state
Postoperative state (after 7-10 days)
Cancer
Tissue transplantation
Other conditions with fever or leukocytosis not caused by bacterial infection (e.g., RA>

Decreased or Normal In Presence of Bacterial Infection
Antibiotic therapy—effectiveness of treatment indicated by reduction of previous elevation, sometimes in <6 hours
Localized infection
Administration of corticosteroids and immunosuppressive drugs (although contrary findings with corticosteroids have also been reported)

Source --- Wallach Interpretation of Diagnostic Tests - Page 453

vivek_patel · Credits: 2160 My Scrapbook

so is the ans NBT...

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