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TFM Roberto Arias MEMORIA PRESENTADA PARA ASPIRAR AL MÁSTER DE CONDICIONANTES GENÉTICOS, NUTRICIONALES Y AMBIENTALES EN EL CRECIMIENTO Y EL DESARROLLO TÍTULO DE LA MEMORIA RECURSOS NUTRICIONALES DE AMÉRICA LATINA PARA EL TRATAMIENTO DE LOS ERRORES INNATOS DEL METABOLISMO INTERMEDIARIO Firmado Roberto Arias Marrón DNI: 72350103-S Línea de Investigación: Nutrición y Metabolismo Centro: Área de Metabolómica del Instituto BioCruces Bizkaia Director del trabajo: Dr. Fernando Andrade Lodeiro DNI: 78899252-Y Firma: Santander a 03 de Julio de 2020 A Fernando, por haberme acogido con los brazos abiertos desde el primer día de las prácticas, y por haberme enseñado, aconsejado y apoyado siempre en mi formación académica y profesional. Has sido el mejor director de trabajo que he podido tener. A Koldo, por todo lo que me ha enseñado, apoyado y ayudado. Pocas veces me he sentido tan valorado a nivel profesional. Me siento afortunado y orgulloso de haber podido aprender tanto de ti. A Olatz, por su profesionalidad y por haber sido un gran apoyo y una gran compañera durante mi estancia en BioCruces Bizkaia. Por último, a todos los niños y niñas del Hospital Universitario de Cruces, haciendo mención especial a sus familias, que luchan día tras día contra la enfermedad. RESUMEN Los errores innatos del metabolismo (EIM) son un grupo de patologías de carácter genético que incluye un amplio espectro de trastornos heterogéneos. El tratamiento nutricional es actualmente una de las principales herramientas terapéuticas disponibles. El objetivo de este estudio consiste en analizar el material técnico y los recursos nutricionales presentes en América Latina para el tratamiento de los Errores Innatos del Metabolismo Intermediario. Los resultados obtenidos muestran una significativa restricción de los alimentos accesibles para pacientes de patologías metabólicas y un limitado acceso a material técnico con recursos nutricionales locales y su composición. Es necesario que América Latina, afectada en su capacidad de investigación, diagnóstico y tratamiento de los EIM por su delicada situación económica, política, social y geográfica, avance en la investigación y el estudio de este grupo de patologías. Palabras clave: Fenilcetonuria, Acidemias orgánicas, Tirosinemia, Galactosemia, Fructosemia, Metabolismo, Tratamiento, Nutrición. ABSTRACT Inborn errors of metabolism (IEM) are a group of pathologies of genetic nature that include a wide spectrum of heterogeneous disorders. Nutritional treatment is currently one of the main therapeutic tools available. The objective of this study is to analyze the technical material and nutritional resources present in Latin America for the treatment of Inborn Errors of Intermediate Metabolism. The results obtained show a significant reduction of the foods accessible to patients suffering from metabolic pathologies and limited access to technical material linked to local nutritional resources. It is necessary that Latin America, affected in its capacity of research, diagnosis and treatment of IEM due to its delicate economic, political, social and geographical situation, move forward in the research and study of this group of pathologies. Keywords: Phenylketonuria, Organic Acidemias, Tyrosinemia, Galactosemia, Fructosemia, Metabolism, Treatment, Nutrition 1 INDICE 1. INTRODUCCIÓN ................................................................................................................... 3 2. OBJETIVOS .......................................................................................................................... 5 3. JUSTIFICACIÓN ................................................................................................................... 5 4. PREGUNTAS DE INVESTIGACIÓN ..................................................................................... 6 5. MARCO TEÓRICO ................................................................................................................ 7 5.1 METABOLISMOS ENERGÉTICOS .............................................................................. 7 5.2 ERRORES INNATOS DEL METABOLISMO (EIM) ...................................................... 8 5.2.1 Aminoacidopatías congénitas ................................................................................... 9 5.2.1.1 Fenilcetonuria (PKU) ............................................................................................... 10 5.2.1.2 Tirosinemias ............................................................................................................ 13 5.2.2 Acidemias orgánicas ............................................................................................... 16 5.2.2.1 Acidemia Propiónica y Acidemia Metilmalónica .................................................. 16 5.2.3 Errores innatos del metabolismo de los carbohidratos ........................................... 18 5.2.3.1 Galactosemia ....................................................................................................... 18 5.2.3.2 Defectos del metabolismo de la fructosa ............................................................ 20 5.3 TRATAMIENTO NUTRICIONAL DE LOS EIM ........................................................... 22 5.3.1 Tratamiento nutricional de la fenilcetonuria (PKU) .................................................. 22 5.3.2 Tratamiento nutricional de la tirosinemia tipo 1 ....................................................... 24 5.3.3 Tratamiento nutricional de las acidemias orgánicas ............................................... 25 5.3.4 Tratamiento nutricional de la galactosemia ............................................................. 26 5.3.5 Tratamiento nutricional de la Fructosemia .............................................................. 27 6. METODOLOGÍA .................................................................................................................. 29 7. RESULTADOS .................................................................................................................... 31 8. DISCUSIÓN ......................................................................................................................... 49 9. CONCLUSIÓN ..................................................................................................................... 59 10. BIBLIOGRAFÍA ................................................................................................................... 61 11. ANEXOS............................................................................................................................. 67 2 1. INTRODUCCIÓN Los errores innatos del metabolismo (EIM) o también denominadas enfermedades metabólicas, hacen referencia a un grupo de patologías de carácter genético que incluye más de 500 trastornos heterogéneos, con una incidencia global estimada de 1/2500 (1,2). La primera aproximación establecida para definir estos trastornos fue desarrollada por Sir Archibald Garrod. Tras conocer los orígenes genéticos y bioquímicos de la alcaptonuria, la cistinuria, la pentosuria y el albinismo, introdujo el concepto de “un gen, una enfermedad”, en su trabajo "Errores innatos del metabolismo", presentado en el Royal College of Physicians en 1908. No obstante, en estudios posteriores se evidenció que no existe correlación entre genotipo-fenotipo en los EIM, y se observaron diferentes fenotipos para las mismas variaciones genéticas, sugiriendo la posible influencia de factores ambientales, desacreditando la teoría de Garrod (1,3). Actualmente el efecto patológico de los EIM se comprende a través de aspectos como la deficiencia de un producto o enzima esencial, los efectos tóxicos sistémicos de los metabolitos circulantes y la activación o inhibición de un metabolismo alternativo, los cuales inducen el funcionamiento erróneo en alguna de las rutas bioquímicas del organismo humano destinadas a metabolizar lípidos, hidratos de carbono, proteínas o una combinación de las mismas (3). La transmisión de la mutación genética es habitualmente de carácter autosómica recesiva, pero también se han descrito trastornos autosómicos dominantes ligados al cromosoma X, y otros casos que pueden incluir mutaciones en el ADN mitocondrial. La gran diversidad de las vías metabólicas dificulta el diagnóstico de estas patologías. Su aparición de carácter individual es extraña, sin embargo se piensa que su incidencia acumulada es alta, aproximadamente de 1/500 (2). Los EIM pueden desencadenar una alta tasa de mortalidad si no se perciben a tiempo, pudiendo obtener resultados positivos si el diagnóstico es temprano y se recibe una atención médica y tratamientos ininterrumpidos que mejoren la calidad de vida. Los servicios y la atención requerida es multidisciplinaria y casi siempre se basa en la opinión de expertos (4). Las terapias actualizadas para el tratamiento de los EIM abarcan una serie de sistemas definidos para superar las alteraciones bioquímicas causadas por el bloqueo metabólico primario. Las intervenciones más consistentes son el reemplazo directo de enzimas y compuestos mediante su aplicación por vía directa y la reducción de los 3 metabolitos tóxicos a través de la modulación dietética de los precursores enzimáticos (1–3). Las alternativas existentes en el tratamiento dietético, pilar fundamental para el manejo de los trastornos metabólicos, se fundamentan en, la limitación o supresión de un nutriente cuyos derivados provocan el acumulo de metabolitos tóxicos, la administración de un producto determinado en caso de que su metabolito final sea necesario para
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