{"id":114727,"date":"2013-04-10T00:00:00","date_gmt":"2013-04-10T00:00:00","guid":{"rendered":"https:\/\/www.deberes.net\/tesis\/sin-categoria\/estudio-descriptivo-mutacional-de-pacientes-hemofa%c2%adlicos-en-la-region-de-murcia\/"},"modified":"2013-04-10T00:00:00","modified_gmt":"2013-04-10T00:00:00","slug":"estudio-descriptivo-mutacional-de-pacientes-hemofa%c2%adlicos-en-la-region-de-murcia","status":"publish","type":"post","link":"https:\/\/www.deberes.net\/tesis\/murcia\/estudio-descriptivo-mutacional-de-pacientes-hemofa%c2%adlicos-en-la-region-de-murcia\/","title":{"rendered":"Estudio descriptivo mutacional de pacientes hemof\u00edlicos en la regi\u00f3n de murcia"},"content":{"rendered":"<h2>Tesis doctoral de <strong> Faustino Garcia Candel <\/strong><\/h2>\n<p>Introducci\u00f3n: la hemofilia se caracteriza por una deficiencia de la actividad de factor viii de la coagulaci\u00f3n (hemofilia a) o de factor ix de la coagulaci\u00f3n (hemofilia b). La preValencia estimada es de alrededor de 1 por 5000 varones nacidos (para hemofilia a) y de 1 por 30000 varones nacidos (para hemofilia b). La transmisi\u00f3n es como un rasgo recesivo ligado al cromosoma x (herencia ligada al sexo). la cl\u00ednica se basa en la aparici\u00f3n de sangrados recurrentes, cuya intensidad y frecuencia est\u00e1n en estrecha relaci\u00f3n con la severidad del defecto de la prote\u00edna fviii o fix. La complicaci\u00f3n m\u00e1s temida actualmente en el tratamiento de la enfermedad es la aparici\u00f3n de aloanticuerpos contra el factor viii\/fix administrado y que aparece m\u00e1s frecuentemente en las formas graves. el gen del fviii (f8) se encuentra en la porci\u00f3n telom\u00e9rica distal del brazo largo del cromosoma x, en la banda xq28. Consta de 26 exones que se extienden a lo largo de unas 186.000 pares de bases. las alteraciones gen\u00e9ticas en el gen del fviii (f8) se pueden clasificar en: grandes reaordenamientos. Inserciones o deleciones, y sustituciones simples. La alteraci\u00f3n recurrente m\u00e1s importante cl\u00ednicamente es un reordenamiento que afecta al intr\u00f3n 22 (inversi\u00f3n del intr\u00f3n 22), afectando aproximadamente al 45% de todas las formas graves de hemofilia a. el gen del fix (f9) se encuentra localizado en la regi\u00f3n telom\u00e9rica del brazo largo del cromosoma x, en la banda xq27, tiene un tama\u00f1o cercano a las 34 kb y consta de 8 exones y 7 intrones. Las mutaciones en el gen f9 se pueden clasificar en: mutaciones puntuales, mutaciones hotspots, mutaciones que truncan la prote\u00edna y  mutaciones que afectan a la regi\u00f3n promotora. El grupo m\u00e1s frecuente de alteraciones es el de las mutaciones puntuales. el estudio de las portadoras de hemofilia constituye una parte fundamental en el manejo de esta patolog\u00eda, tanto para hacer un adecuado asesoramiento gen\u00e9tico como para prevenir posibles eventos hemorr\u00e1gicos en esta poblaci\u00f3n. para el diagn\u00f3stico molecular de la hemofilia existen dos tipos de metodolog\u00edas: t\u00e9cnicas indirectas y la secuenciaci\u00f3n nucleot\u00eddica directa. objetivo: el objetivo principal es estudiar las mutaciones que afectan a los pacientes hemof\u00edlicos de la regi\u00f3n de murcia. material y m\u00e9todo: estudiamos a 73 pacientes de un total de 80 censados, con una mediana de edad de 26 a\u00f1os (rango 3-76 a\u00f1os). De las 53 familias no relacionadas censadas, estudiamos a 46. La dosificaci\u00f3n de los factores viii y ix se realiz\u00f3 en el laboratorio de hemostasia del hospital cl\u00ednico universitario virgen de la arrixaca, que cuenta con la acreditaci\u00f3n de la norma 15189 por enac. Los afectados fueron distribuidos por familias no relacionadas, detect\u00e1ndose en cada una de ellas a las portadoras posibles y obligadas mediante la relaci\u00f3n del \u00e1rbol geneal\u00f3gico. El estudio gen\u00e9tico se llev\u00f3 a cabo tanto a los afectados como a las portadoras. Para hemofilia a se estudi\u00f3 en primer lugar la presencia o ausencia de  inversi\u00f3n del intr\u00f3n 22 y del intr\u00f3n 1 mediante pcr inversa. En los casos negativos se realiz\u00f3 secuenciaci\u00f3n directa del gen f8. para hemofilia b se realiz\u00f3 secuenciaci\u00f3n directa del gen f9 mediante pcr. resultados: en nuestra regi\u00f3n existen 80 pacientes hemof\u00edlicos vivos distribuidos en 53 familias. 65 (81,2%) tienen hemofilia a y 15 (18,5%) hemofilia b, con una mediana de edad de 28 a\u00f1os (1 mes-76 a\u00f1os). Existen 28 afectados con hemofilia a grave, 7 con hemofilia a moderada, 30 con hemofilia a leve, 8 con hemofilia b grave, 1 con hemofilia b moderada y 6 con hemofilia b leve. de los 73 pacientes estudiados (distribuidos en 46 familias) hemos encontrado la mutaci\u00f3n causante de la enfermedad en todos ellos y se ha confirmado el estado de portadora mediante estudio gen\u00e9tico en 102 casos de los 149 miembros femeninos de las distintas familias. El grupo de portadoras m\u00e1s numeroso corresponde al de edades entre 16 y 45 a\u00f1os. De las mutaciones encontradas en la poblaci\u00f3n estudiada, las m\u00e1s frecuentes son las de tipo missense, seguidas por la inversi\u00f3n del intr\u00f3n 22. Se han encontrado 11 mutaciones no descritas en los registros internacionales, correspondiendo la mayor parte a mutaciones de tipo missense. Existe una incidencia de casos sin antecedentes familiares del 52,2%, con predominio en los casos de hag (28,3%). No se ha encontrado la alteraci\u00f3n gen\u00e9tica en la madre en 4 casos. conclusiones: se ha podido determinar la alteraci\u00f3n gen\u00e9tica causante de la hemofilia en todos los pacientes estudiados, siendo el tipo de mutaci\u00f3n m\u00e1s frecuente la missense.  existe un porcentaje importante de casos espor\u00e1dicos, la mayor\u00eda con hemofilia a grave, en los que se ha determinado los casos de portadoras y poder realizar un adecuado asesoramiento gen\u00e9tico. La incidencia de inhibidores ha sido del 11%, algunos casos asociados a mutaciones no descritas en registros internacionales. Por otra parte, el algoritmo de estudio gen\u00e9tico dise\u00f1ado para este trabajo ha resultado efectivo. introduction: hemophilia is characterized by a deficiency in the activity of coagulation factor viii (hemophilia a) or coagulation factor ix (hemophilia b). The estimated prevalence is about 1 per 5000 male births (hemophilia a) and 1 in 30,000 male births (for hemophilia b). The transmission as a recessive  x-linked (sex-linked inheritance). the clinic is based on the occurrence of recurrent bleeding and the intensity and frequency are closely related to the severity of the defect protein. The most feared complication in the treatment of the disease is the occurrence of alloantibodies against factor viii \/ fix administered and most frequently occurring in severe forms. the f8 gene is in the distal portion of the long arm of chromosome x in the xq28 band. Consists of 26 exons spanning along some 186,000 base pairs. genetic alterations in the f8 gene can be classified as: gross gene rearrangements. Insertions or deletions, and simple substitutions. The most important mutation is the recurrent rearrangement involving the intron 22 (intron 22 inversion), affecting approximately 45% of all severe forms of hemophilia a. the f9 gene is located at the telomeric region of the long arm of the x chromosome, on xq27 band and has a size close to 34 kb and consists of 8 exons and 7 introns. Mutations in this gene can be classified into: point mutations, hotspots mutations, protein truncating mutations and promoter region mutations. The most common group of disorders is the point mutations. the study of carriers of hemophilia is an essential part in the management of this condition, both for adequate genetic counseling and to prevent possible bleeding events in this population. for molecular diagnosis of haemophilia two types of methodologies: indirect techniques and direct nucleotide sequencing objective: the main objective is to study mutations affecting hemophiliacs patients in the region of murcia. material and methods: we studied 73 patients with a total of 80 census, with a median age of 26 years (range 3-76 years). Of the 53 unrelated families surveyed, we studied 46. The dosage of factor viii and ix was held at the hemostasis laboratory university hospital virgen de la arrixaca, with the accreditation of the standard 15189 by enac. These patients were distributed in unrelated families, detected in each of the carriers by performing the pedigree. The genetic study was conducted both affected and carriers. In hemophilia a is first examined the presence or absence of intron 22 inversion  and intron 1 inversion by inverse pcr. In negative cases direct sequencing was performed of f8 gene. hemophilia b direct sequencing was performed by pcr of f9 gene. results: in our region there are 80 living hemophiliacs distributed in 53 families. 65 (81.2%) have hemophilia a and 15 (18.5%) hemophilia b, with a median age of 28 years (1 month-76 years). There are 28 affected with severe hemophilia a, hemophilia 7 with moderate, 30 with mild hemophilia a, 8 with severe haemophilia b, one with moderate hemophilia b and  6 with mild hemophilia b. of the 73 patients studied (distributed in 46 families) have found the mutation in all of them and confirmed the carrier status by genetic study in 102 cases of the 149 female members of the different families. The largest carrier group corresponds to ages 16 and 45. Of the mutations found in the study population, the most common are missense, followed by the inversion of intron 22. We have found 11 mutations not described in the international records, being missense mutationts the most frequent. There is an incidence of cases with no family history of 52.2%, predominantly in severe hemophilia a (28.3%). In four mother no genetic alteration was found. conclusions: it was possible to determine the genetic alteration responsible for hemophilia in all patients studied, being the most common type of the missense mutation. there is a significant percentage of sporadic cases, most with severe hemophilia a. In this cases, the carrier diagnosis is essential for an adequate genetic counseling. The incidence of inhibitors was 11%, some cases associated with mutations not described in international registrations. Moreover, genetic analysis algorithm designed for this work has been effective.<\/p>\n<p>&nbsp;<\/p>\n<h3>Datos acad\u00e9micos de la tesis doctoral \u00ab<strong>Estudio descriptivo mutacional de pacientes hemof\u00edlicos en la regi\u00f3n de murcia<\/strong>\u00ab<\/h3>\n<ul>\n<li><strong>T\u00edtulo de la tesis:<\/strong>\u00a0 Estudio descriptivo mutacional de pacientes hemof\u00edlicos en la regi\u00f3n de murcia <\/li>\n<li><strong>Autor:<\/strong>\u00a0 Faustino Garcia Candel <\/li>\n<li><strong>Universidad:<\/strong>\u00a0 Murcia<\/li>\n<li><strong>Fecha de lectura de la tesis:<\/strong>\u00a0 04\/10\/2013<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n<h3>Direcci\u00f3n y tribunal<\/h3>\n<ul>\n<li><strong>Director de la tesis<\/strong>\n<ul>\n<li>Eduardo Tizzano Ferrari<\/li>\n<\/ul>\n<\/li>\n<li><strong>Tribunal<\/strong>\n<ul>\n<li>Presidente del tribunal: javier Batlle forondona <\/li>\n<li>v\u00edctor Jim\u00e9nez yuste (vocal)<\/li>\n<li>Mar\u00eda isabel Zuazu jausoro (vocal)<\/li>\n<li>Ana Mar\u00eda Garcia hernandez (vocal)<\/li>\n<\/ul>\n<\/li>\n<\/ul>\n<p>&nbsp;<\/p>\n","protected":false},"excerpt":{"rendered":"<p>Tesis doctoral de Faustino Garcia Candel Introducci\u00f3n: la hemofilia se caracteriza por una deficiencia de la actividad de factor viii [&hellip;]<\/p>\n","protected":false},"author":1,"featured_media":0,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":{"site-sidebar-layout":"default","site-content-layout":"","ast-site-content-layout":"","site-content-style":"default","site-sidebar-style":"default","ast-global-header-display":"","ast-banner-title-visibility":"","ast-main-header-display":"","ast-hfb-above-header-display":"","ast-hfb-below-header-display":"","ast-hfb-mobile-header-display":"","site-post-title":"","ast-breadcrumbs-content":"","ast-featured-img":"","footer-sml-layout":"","theme-transparent-header-meta":"","adv-header-id-meta":"","stick-header-meta":"","header-above-stick-meta":"","header-main-stick-meta":"","header-below-stick-meta":"","astra-migrate-meta-layouts":"default","ast-page-background-enabled":"default","ast-page-background-meta":{"desktop":{"background-color":"var(--ast-global-color-4)","background-image":"","background-repeat":"repeat","background-position":"center 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