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      Caracterización clínica y genético-molecular de un paciente con enfermedad granulomatosa crónica ligada al X: Reporte de una nueva mutación asociada al splicing.Caso clínico Translated title: Clinical, genetic and molecular characterization of the X-linked chronic granulomatous disease: A case report of a new splicing mutation

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          Abstract

          Introducción: La Enfermedad Granulomatosa Crónica (EGC) se presenta como consecuencia de mutaciones en los genes que codifican 5 de las subunidades del sistema NADPH oxidasa humano. Su forma más común es causada por cambios en el gen CYBB que codifica gp91 phox. Objetivo: Identificar el defecto molecular que lleva a la presentación de la EGC. Caso clínico: Paciente de sexo masculino con antecedentes de enfermedad diarreica aguda y abscesos perianales recurrentes desde los 2 meses. A los 6 meses, presentó una inflamación crónica del colon y colitis bacteriana. A los 3 años tenía infecciones en las vías respiratorias inferiores y perianales. Estudio compatible con EGC. El análisis del ADNc identificó expresión anormal del ARNm, lo cual se confirmó al realizar la secuenciación. Específicamente se observó la ausencia del exón 2. Adicionalmente, los datos de la secuenciación del ADNg identificaron una alteración en el sitio aceptor de "splicing" del intrón 1, que incluye una deleción seguida de la inserción de 3 nucleótidos (c.46-14_-11delTTCT insGAA). Conclusiones: Se presenta el primer estudio molecular de un paciente con EGC por defecto de "splicing" reportado en Colombia. La definición de la mutación y su correlación con el fenotipo es importante para proveer una apropiada consejería genética al paciente y su familia.

          Translated abstract

          Chronic granulomatous disease (CGD) is caused by mutations in the genes that encode five of the subunits of the human NADPH oxidase. The most common form is caused by mutations in CYBB, the human gene encoding gp 91 phox. Objective: To identify the molecular defects causing CGD. Case report: A male patient with a history of acute diarrhea and recurrent perianal abscess since two months old. At 6 months, the patient presented a chronic inflammatory disease of the colon and bacterial colitis. After three years, he developed infections in the lower and perianal respiratory tract. The cDNA analysis identified abnormal mRNA expression, which was confirmed by sequencing. Specifically the exclusion of exon 2 was observed. Additionally, gDNA sequencing identified an alteration in the acceptor splice site of intron 1, including a deletion followed by insertion of three nucleotides (c.46-14_-11delTTCT insGAA). Conclusions: The first molecular study of a patient with CGD due to splicing pattern change, reported in Colombia, is presented. The definition of the mutation and its correlation with the phenotype is essential to provide appropriate genetic counseling to patients and their families.

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          Most cited references41

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          Genetic, biochemical, and clinical features of chronic granulomatous disease.

          The reduced nicotinamide dinucleotide phosphate (NADPH) oxidase complex allows phagocytes to rapidly convert O2 to superoxide anion which then generates other antimicrobial reactive oxygen intermediates, such as H2O2, hydroxyl anion, and peroxynitrite anion. Chronic granulomatous disease (CGD) results from a defect in any of the 4 subunits of the NADPH oxidase and is characterized by recurrent life-threatening bacterial and fungal infections and abnormal tissue granuloma formation. Activation of the NADPH oxidase requires translocation of the cytosolic subunits p47phox (phagocyte oxidase), p67phox, and the low molecular weight GT-Pase Rac, to the membrane-bound flavocytochrome, a heterodimer composed of the heavy chain gp91phox and the light chain p22phox. This complex transfers electrons from NADPH on the cytoplasmic side to O2 on the vacuolar or extracellular side, thereby generating superoxide anion. Activation of the NADPH oxidase requires complex rearrangements between the protein subunits, which are in part mediated by noncovalent binding between src-homology 3 domains (SH3 domains) and proline-rich motifs. Outpatient management of CGD patients relies on the use of prophylactic antibiotics and interferon-gamma. When infection is suspected, aggressive effort to obtain culture material is required. Treatment of infections involves prolonged use of systemic antibiotics, surgical debridement when feasible, and, in severe infections, use of granulocyte transfusions. Mouse knockout models of CGD have been created in which to examine aspects of pathophysiology and therapy. Gene therapy and bone marrow transplantation trials in CGD patients are ongoing and show great promise.
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            NADPH oxidase

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              Recognition and management of dyslipidemia in children and adolescents.

              Cardiovascular disease (CVD) remains the number one cause of death in the United States. The origins of atherosclerosis and CVD begin in childhood. Dyslipidemia and obesity are endemic in American youth and require urgent action. A detailed literature search from 1985-2008 was performed using PubMed and subsequent reference searches of retrieved articles. Selection of included articles was based on rigor of scientific design, adequate sample size, quality of the data, statistical analysis, and hypothesis testing. CVD risk factors in children predict pathological lesions of atherosclerosis in young adults, and their clinical manifestations, as judged by carotid intima medial thickness, coronary artery calcium, or brachial flow-mediated dilatation. About half the offspring of a parent with premature CVD have a primary dyslipidemia. However, use of family history to identify such youth will miss the majority of children with dyslipidemia. Treatment of dyslipidemia starts with a low-fat diet supplemented with water-soluble fiber, plant stanols, and plant sterols, weight control, and exercise. Drug therapy with inhibitors of hydroxymethylglutaryl coenzyme A reductase, bile acid sequestrants (BAS), and cholesterol absorption inhibitors can be considered in adolescents with a positive family history of premature CVD and a low-density lipoprotein cholesterol of more than 160 mg/dL. Such dietary and drug therapy appears safe and efficacious and is likely to retard atherosclerosis. Early identification and treatment of youth at risk for early atherosclerosis will require an integrated assessment of predisposing CVD risk factors and a comprehensive universal screening and treatment program.
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                Author and article information

                Journal
                rcp
                Revista chilena de pediatría
                Rev. chil. pediatr.
                Sociedad Chilena de Pediatría (Santiago, , Chile )
                0370-4106
                April 2014
                : 85
                : 2
                : 213-221
                Affiliations
                [02] Medellín orgnameGrupo de Neurociencias de Antioquia Colombia
                [01] Medellín orgnameUniversidad de Antioquia orgdiv1Grupo de Inmunodeficiencias primarias Colombia
                Article
                S0370-41062014000200012 S0370-4106(14)08500200012
                10.4067/s0370-41062014000200012
                943ea462-06dc-4231-8d5c-ad59c28b0acc

                This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.

                History
                : 31 July 2013
                : 24 January 2014
                Page count
                Figures: 0, Tables: 0, Equations: 0, References: 25, Pages: 9
                Product

                SciELO Chile

                Categories
                CASOS CLINICOS

                NADPH oxidasa,gp 91 phox,Enfermedad Granulomatosa crónica,splicing,Chronic granulomatous disease,gp91 phox,NADPH oxidase

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