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M Áster En Biotecnología Y Biom Edicina Centro de Estudios de Postgrado Máster en Biotecnología y Biomedicina Alumno/a: Dpto: Tutor/a: ENCEFALOPATÍAS INFANTILES FARMACOLÓGICA G Biología Biología Experimental Esteban José Francisco Ruiz ENOTIPO Trabajo Fin de Máster Centro de Centro Estudios dePostgrado Paula Gregorio Pablos Universidad deJaén Universidad Julio de 2020 STXBP1. Y EN Y RESPUESTA EL EPILÉPTICAS SÍNDROME EN LAS UNIVERSIDAD DE JAÉN MÁSTER EN BIOTECNOLOGÍA Y BIOMEDICINA TRABAJO FIN DE MÁSTER GENOTIPO Y RESPUESTA FARMACOLÓGICA EN LAS ENCEFALOPATÍAS EPILÉPTICAS INFANTILES Y EN EL SÍNDROME STXBP1. Alumno/a: Paula Gregorio Pablos Tutor/a: Francisco José Esteban Ruiz 2 Resumen Las encefalopatías epilépticas infantiles tempranas son un conjunto de encefalopatías epilépticas graves asociadas con la edad, caracterizadas por presentar epilepsia en las primeras semanas o meses de vida, espasmos tónicos y un patrón de brote-supresión en el electroencefalograma. Estos síndromes suelen estar acompañados por un retraso en el desarrollo y un deterioro intelectual. Dentro de esta agrupación encontramos el síndrome STXBP1, cuyas anomalías fenotípicas principales son la discapacidad intelectual, la epilepsia y los trastornos del movimiento. En la actualidad, estos síndromes son difíciles de diagnosticar y no tienen cura, por lo que su tratamiento se centra principalmente en paliar los síntomas. El objetivo principal de este trabajo es establecer una relación entre el genotipo y la respuesta farmacológica de las personas con EIEE y en concreto, del síndrome STXBP1, con el fin de poder ofrecer un tratamiento personalizado. Para alcanzar este objetivo, construimos redes de interacción con los genes asociados a las EIEE y sus fármacos asociados, realizamos un estudio detallado de los fármacos prescritos y analizamos la prevalencia de las mutaciones en la población relacionándola con el número de fármacos asociados. Los resultados obtenidos muestran que los fármacos más empleados en el tratamiento de las EIEE son los antiepilépticos, en concreto los de primera generación. Además, este estudio evidencia la falta de información actual sobre las respuestas farmacológicas y la incidencia de las mutaciones de las EIEE en la población, lo que dificulta las investigaciones en este ámbito. Palabras clave: EIEE, STXBP1, antiepilépticos, respuesta farmacológica. 3 Abstract Early childhood epileptic encephalopathies are a group of severe epileptic encephalopathies associated with age, characterized by presenting epilepsy in the first weeks or months of life, tonic spasms and a suppression-burst pattern on the electroencephalogram. These syndromes are often accompanied by delayed development and intellectual decline. Within this group we find the STXBP1 syndrome, whose main phenotypic abnormalities are intellectual disability, epilepsy and movement disorders. Currently, these syndromes are difficult to diagnose and have no cure, so their treatment is mainly focused on relieve the symptoms. The main objective of this work is to establish a relationship between the genotype and the pharmacological response of people with EIEE and, specifically, of STXBP1 syndrome, in order to be able to offer personalized treatment. To achieve this goal, we built interaction networks with the genes associated with the EIEE and their associated drugs, we carried out a detailed study of the prescribed drugs and we analyzed the prevalence of mutations in the population, relating it to the number of associated drugs. The results obtained show that the drugs most used in the treatment of EIEE are antiepileptics, specifically those of the first generation. Furthermore, this study evidences the lack of current information on pharmacological responses and the incidence of EIEE mutations in the population, which makes research in this area difficult. Keywords: EIEE, STXBP1, antiepileptics, pharmacological response. 4 Índice 1. Introducción............................................................................................................................6 1.1 Encefalopatía epiléptica infantil temprana.......................................................................6 1.2 Encefalopatía epiléptica STXBP1..................................................................................10 2. Objetivos...............................................................................................................................14 3. Materiales y métodos............................................................................................................15 3.1 Extracción de información.............................................................................................15 3.2 Construcción de redes de interacción.............................................................................15 3.3 Estudio de prevalencia poblacional................................................................................15 3.4 Análisis de los fármacos prescritos en las EIEE.............................................................16 4. Resultados.............................................................................................................................17 4.1 Redes de interacción.......................................................................................................18 4.2 Análisis de prevalencia poblacional...............................................................................23 4.3 Análisis de los fármacos prescritos................................................................................29 5. Discusión...............................................................................................................................32 6. Conclusiones.........................................................................................................................33 7. Bibliografía...........................................................................................................................34 8. Anexo I..................................................................................................................................39 9. Anexo II.................................................................................................................................42 10. Anexo III.............................................................................................................................69 11. Fuentes de financiación.......................................................................................................71 12. Curriculum Vitae.................................................................................................................71 5 1. Introducción 1.1 Encefalopatía epiléptica infantil temprana La encefalopatía epiléptica (EE) se puede definir como aquella actividad epiléptica que participa en el deterioro cognitivo, conductual y psicomotor del cerebro en desarrollo (Duszyc et al., 2015). También se caracteriza por la aparición de convulsiones intratables y anormalidades en el electroencefalograma (EEG), y los pacientes experimentan un daño severo con un alto riesgo de comorbilidades y mal pronóstico (Nashabat et al., 2019; Zhong et al., 2019). La encefalopatía epiléptica infantil temprana (EIEE, por sus siglas en inglés) y la encefalopatía mioclónica temprana (EME) comprenden un grupo de encefalopatías epilépticas de inicio temprano de tipo brote-supresión (EOEE-SB) (Olson et al., 2017). Ambos tipos de encefalopatías epilépticas comparten características como: (i) la edad de inicio; (ii) el patrón brote-supresión (brotes de alto voltaje de ondas lentas mezcladas con picos multifocales, alternando con fases de supresión isoeléctrica (Lemattre et al., 2019)) en el electroencefalograma (EEG); (iii) y un retraso psicomotor severo y pronóstico grave, lo que hace difícil su identificación. Entre los puntos clave para discernir las EIEE de las EME se encuentran la etiología, el tipo de crisis epilépticas -que prevalece en las primeras crisis clínicas-, la influencia de la vigilia y el sueño durante el patrón brote-supresión (BS) en el EEG, así como la amplitud de la fase de estallido y de supresión. Las EIEE suelen presentar convulsiones tónicas en su inicio, su principal etiología son anormalidades cerebro-estructurales, su patrón BS en los EEG no está influenciado por los estados de vigilia y sueño, y a veces se puede observar una mayor amplitud de la fase de brote y una menor duración de la fase de supresión en los EEG, en comparación con los casos de EME. Sin embargo, las EME se suelen presentar en forma de convulsiones mioclónicas en el inicio de la enfermedad, están más relacionadas con trastornos metabólicos y el patrón BS predomina durante el sueño (Djukic et al., 2006; Chen et al., 2001; Al-Futaisi et al., 2005). En 1976 Ohtahara et al. describieron por primera vez una EIEE con un patrón de BS en el EEG (Djukic et al., 2006). En 1987, Clarke confirmó en once pacientes las características de esta enfermedad y la nombró síndrome de Ohtahara (Aviña &Hernández, 2007). Finalmente, en 2001, la liga internacional contra la Epilepsia (ILAE) incluyó este síndrome 6 como una entidad específica dentro de las EIEE (Engels, 2001), aunque aún en la actualidad se sigue hablando de síndrome de Ohtahara para referirse a las EIEE (Tavyev Asher & Scaglia, 2012). Históricamente, las EIEE se clasificaron en cinco síndromes principales: síndrome de Ohtahara, síndrome de West, síndrome de Lennox-Gastaut, síndrome de Dravet y síndrome de Landau-Kleffner (Nashabat et al., 2019). Las encefalopatías epilépticas infantiles tempranas
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