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CHRONIC GRANULOMATOUS DISEASE CGD Pathogenesis and Diagnosis

Topics to be considered. Review of NADPH Oxidase PathwayMutations in CGD PatientsPathogenesis in CGD and clinical characteristicsDiagnosis of CGDTreatment of CGDCase Study. Chronic Granulomatous Disease. Rare (1/200,000) inherited disorder of the reduced nicotinamide dinucleotide phosphate oxid

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CHRONIC GRANULOMATOUS DISEASE CGD Pathogenesis and Diagnosis

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    1. CHRONIC GRANULOMATOUS DISEASE (CGD) Pathogenesis and Diagnosis

    2. Topics to be considered Review of NADPH Oxidase Pathway Mutations in CGD Patients Pathogenesis in CGD and clinical characteristics Diagnosis of CGD Treatment of CGD Case Study

    3. Chronic Granulomatous Disease Rare (1/200,000) inherited disorder of the reduced nicotinamide dinucleotide phosphate oxidase complex (NADPH) - may be higher Phagocytes defective in production of microbicidal reactive oxidant superoxide anion and metabolites (hydrogen peroxide, hydroxyl anion, & hypohalous acid Patients suffer from life-threatening bacterial & fungal infections. Dramatic inflamatory response leads to granuloma formation

    4. CGD - History First described in 1957 by Good et. al. As fatal granulomatous disease of childhood CGD granulomas had similarities to other granuloma forming diseases (Wegener granulomatosis, brucellosis, sarcoidosis, Hodgkins disease, etc.) Combination of recurrent suppurative and inflammatory complications in childhood recognized - distinct clinical syndrome Originally thought to be X-linked as only diagnosed in boys

    5. History continued 1960s CGD established as a disease of phagocytes Neutrophils exhibit normal phagocytic activity Bacteriocidal activity against S. aureus impaired 1990s to present - Actual defects elucidated CGD genetically heterogeneous, caused by mutation in any one of four structural components of NADPH oxidase complex Mouse knockout models created Gene therapy trials now underway

    8. Current Cellular Phenotype & Genotype in CGD

    9. Mutations in CGD In X91 103 specific mutations identified in 13 exons of gp91phox CYBB gene 11% deletions 24% frameshifts 23% nonsensense 17% splice region 23% missense 2% regulatory region Approximately 90% come from X linked carriers 10% from de novo mutations X linked CDG = Heterogeneous spectrum of mutations Similar heterogeneity for the p22 phox gene CYBA and p67 phox CGD gene NCF2. In contrast, p47 phox CGD - majority due to GT deletion (exon two in NCF1 gene) - frameshift yielding premature stop codon at amino acid 51.

    11. Pathogens in CGD Recurrent infections with catalase producing pathogens (Staph. Aureus, Aspergillus sp. ) Catalase negative pathogens can not degrade their own H2O2 providing exogenous source hypohalous acid formation Other factors besides catalase Not susceptible to all catalase + organisms CGD knockout mice - Catalase-deletant strains of Aspergillus nidulans as virulent as wild type

    12. Pathogens in CGD

    13. Pathogens in CGD

    15. Inflammatory Complications in CGD Chronic inflammation skin ulceration, pneumonitis, inflammatory bowel disease. Exuberant & persistent tissue granuloma formation Mechanism of abnormal inflammation - largely unknown Inability of CGD neutrophils to inactivate proinflammatory chemoattractants via reactive oxidants

    16. Laboratory Diagnosis

    17. CGD by Flow Cytometry Small whole blood sample is stimulated to undergo the oxidative burst with phorbol myristate acetate in the presence of Dye. Dihydrorhodamine123 when oxidized is fluorescent. Fluorescence is quantitated. Results expressed as ratio of Fl. Stimulated over Fl. Unstimulated. CGD test by Flow Cytometry can detect CGD patients, carriers, and can suggest the genotype of the CGD patient.

    18. Case Study

    20. Treatment of CGD Prophylaxis with antibiotics trimethoprim-sulfamethoxazole itraconazole Interferon-gamma does not increase NADPH oxidase (1st yes, 2nd large NIH study - no) Augmentation of oxidant-independent antimicrobial pathways TNF, granule protein synthesis, MHC II expression, FC gamma receptors - all increased

    21. Granulocyte transfusion Has been used in life threatening infections No prospective studies Many possible adverse reactions Bone marrow transplantation Curative 60% of time Due to morbidity and mortality - not routine use May be revisited with stem cell transplantation Treatment of CGD

    22. Gene Therapy Ideal candidate for hematopoietic stem cell gene therapy engraftment of stable normal myeloid stem cell is curative only 3-10% normal neutrophils required for normal protection Treatment of CGD

    23. NIH Gene Therapy Clinical Trial 5 patients with p47phox deficient CGD Autologous CD34 peripheral blood stem cells transduced in vitro with retrovirus vector containing p47phox cDNA Infused without bone marrow conditioning .004 to .05% circulating corrected granulocytes 2 of 5 patients had detectable corrected granulocytes after 6 months Treatment of CGD

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