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Programa del encuentro de familias y médicos AESHA - Asociación Española del Síndrome de la Hemiplejia Alternante Aula 10 Edificio Docente Hospital Sant Joan de Déu – Esplugues de Llobregat (Barcelona) Sábado 6 abril 2013 16:30 Presentación Jornada : Campistol J , Fons C 16.45 Novedades en la Hemiplegia Alternante de la Infancia. Campistol J 17.15 El gen ATP1A3 y la hemiplegia alternante. Resultados serie española. Martorell L 18 Proyecto europeo correlación fenotipo-genotipo en la HAI. Ulate A 18.30 Discusión conjunta. Fons C Hemiplejía alternante de la infancia Jaume Campistol Reunión AESHA , Barcelona , abril 2013 ENRAH Casaer,Azou 1984 Verret-Steee 1971 AicardiBourgeois 1993 2005 nEUroped 2009 Heizen 2012 Panagiotaki 2010 AHC HISTORY Kirshenbau 2013 Appropriate Evaluation in Determining the Diagnosis of AHC MRI, MRA, and magnetic resonance spectroscopy To exclude structural and vascular abnormalities (such as Moyamoya syndrome) and metabolic disorders such as MELAS, pyruvate dehydrogenase deficiency or creatine transport disorders CSF neurotransmitter and pterin metabolites, methyltetrahydrofolate To exclude potentially treatable disorder of dopamine biosynthesis or pyridoxal phosphate-responsive symptoms or folate-deficiency states in patients with paroxysmal dystonia and oculomotor abnormalities Metabolic screening (urine organic acids, plasma amino acids, acylcarnitine, blood lactate and pyruvate, CSF lactate, thyrotropin, thyroxine, CSF and plasma glucose levels) To exclude mitochondrial disorders (eg, pyruvate dehydrogenase deficiency, MELAS), periodic paralysis with thyrotoxicosis, or glucose transporter defects 12- to 24-h video EEG monitoring To exclude epileptic causes for abnormal movements; periodic reevaluation indicated for new or evolving episodes or in case of failure to capture episodes Genetic screening (CACNA1A, ATP1A2, or SLC1A3 sequencing/screening) Low yield but may be appropriate in cases where onset is later in childhood (2 y), ictal episodes are infrequent, family history of complex symptoms with migraine, or documented epileptiform events and cerebral edema on MRI Alternating Hemiplegia of Childhood-Related Neural and Behavioural Phenotypes in Na+,K+-ATPase α3 Missense Mutant Mice Kirshenbaun et al 2013 - Validacion modelo animal de raton mutante Myshkin*, con mutación misense en ATP1A3, Na+, K+ ATP asa alfa 3 como causa de AH - Reproducen el modelo humano de HAI - Es posible poder avanzar mas en el conocimiento de los mecanismos fisiopatológicos de la enfermedad - Nuevas opciones terapeuticas ensayos clinicos en animales de experimentación con la enfermedad Los científicos examinaron el ADN de una variedad especial de ratones, conocida como Myshkin, (Volga soviético) descubrieron que el gen ATP1A3 controla la enzima de sodio y potasio, descubriendo que estos ratones tenían la mitad de la cantidad de enzima necesaria para permanecer sanos. Cuando los ratones Myshkin epilépticos fueron cruzados con una variedad de ratones transgénicos , con una copia extra del gen normal ATP1A3, el gen normal adicional contrarrestó el gen fallido, dando lugar a una descendencia que estaba completamente libre de epilepsia. - Mutaciones sin sentido en el gen ATP1A3 que codifican Na+,K+ ATPasa alfa 3 identificada como causa primaria de la HAI - El raton mutante Myshkyn es portador de un cambio de AA (1810N) que afecta la misma posición en Na+K+ -ATPasa alfa 3 como 1810S encontrada en HAI. - Mediante terapia génica se ha visto que el raton M y las mutaciones ATP1A3 muestran anomalias fenotipicas y sintomas similares AHI -Afectacion motora y cognitiva similar en raton M y pacientes con AHI -Compromiso de las conexiones tálamo corticales ( cortex prefrontal) y reducción conectividad tálamo cortical -Confirmación de que las mutaciones ATP1A3 son las responsables AHC y que el raton Myshkin puede ser un punto de partida para explorar y conocer mejor la AHI, los mecanismos de la enfermedad y permitir nuevos ensayos terapeuticos Laan y cols. artículo del tratamiento con TPM+ FNZ en HAI - Ya ensayado en la población española y en ENRAH con HAI HAI y GLUT-1 Dos casos en la literatura CCC, 8 a Episodios atípicos de AHC a partir de 5m vida Retraso desarrollo, microcefalia Fluctuación a lo largo del dia No respuesta a la medicacion ( FNZ) CSF: ligera hipoglucorraquia Mutaciones para GLUT-1 : heterozygota Mutacion para ATP1A3: + Treatment of alternating hemiplegia of childhood with aripiprazole Shereen Haffejee; Paramala J Santosh Developmental Medicine and Child Neurology; Jan 2009; 51, 1; ProQuest Health and Medical Complete Antipsicótico atípico con parcial actvidad dopaminçérgica Otras opciones en AHC FNZ, Aripiprazol, Verapamilo, TPM, Niapricina, Memantina, Amantadina, Haloperidol, Propanolol….. ARIPIPRAZOL(Abilifi) (1,25 mg/d) Antipsicótico atípico con efectos secundarios (tr extrapiramidal, cefalea, somnolencia, akatisia, nauseas, vomitos, constiipación,… Alternating Hemiplegia of Childhood: Early Characteristics and Evolution of a Neurodevelopmental Syndrome Matthew T. Sweney, MDa, Kenneth Silver, MDb, Marion Gerard-Blanluet, MDc, Jean-Michel Pedespan, MDd, Francis Renault, MDe, Alexis Arzimanoglou, MDf, Mylynda Schlesinger-Massart, MDg, Aga J. Lewelt, MDh, Sandra P. Reyna, MDa, Kathryn J. Swoboda, MDa aDepartments of Neurology and Pediatrics, hDepartment of Physical Medicine and Rehabilitation, University of Utah School of Medicine, Salt Lake City, Utah; bDepartments of Pediatrics and Neurology, University of Chicago Hospitals, Chicago, Illinois; cClinical Genetics Unit, Department of Medical Genetics, Assistance Publique-Hoˆpitaux de Paris, Robert Debre´ University Hospital, Paris, France; dDepartment of Pediatrics, Bordeaux University Hospital, Bordeaux, France; eClinical Neurophysiology Unit, Armand-Trousseau Hospital, Paris, France; fDepartment of Pediatric Epilepsy, Sleep and Clinical Neurophysiology and Institute for Children and Adolescents With Epilepsy-Institut DesE´ pilepsies de l‘Enfant et de l‘Adolescent, University Hospitals of Lyon and Institut National de la Sante´ de la Recherche´ Medicale, Dynamique Ce´re´brale et Cognition, Lyon, France; gDepartment of Family Medicine, Oregon Health and Science University, Portland, Ore Diagnostic criteria for classical AHC Onset of symptoms before 18 mo of age Repeated attacks of hemiplegia involving either side of the body Other paroxysmal disturbances including tonic or dystonic spells, oculomotor abnormalities, and autonomic phenomena during bouts in isolation Episodes of bilateral hemiplegia or quadriplegia as generalization of a hemiplegic episode or bilateral from the beginning Immediate disappearance of symptoms upon sleeping, which later may resume after waking Evidence of developmental delay and neurologic abnormalities including choreoathetosis, dystonia, or ataxia Screening Criteria for Early Suspicion of AHC Focal or unilateral paroxysmal dystonia and/or flaccid hemiplegia in the first 6 mo of life Paroxysmal ocular movements including biocular and monocular nystagmus and/or deviation in the first 3 mo of life Absence of epileptiform changes during ictal events CONCLUSIONS AHC is a rare but devastating disease that is difficult to diagnose and even more challenging to treat. Symptoms associated with AHC have a profound impact on affected patients and families. Health resource utilization is substantial in this population, because frequent attacks result in dozens of inpatient admissions or emergency department visits in the course of a year. Empiric medication trials can negatively affect patient health with limited therapeutic gains, particularly when medications are added to an existing regimen, which in itself was already of unclear benefit. The complexity and severity of this disorder makes it imperative that new therapeutic options be explored, preferably in a placebo-controlled fashion. In addition, earlier detection and accurate diagnosis might afford the opportunity to alter what seems to be an unrelenting course. ENRAH 157 PACIENTES CEE con AHC AHC ENRAH nEUroped J. Campistol Servei de Neurología Hospital San Joan de Déu Universitat de Barcelona Proyecto de correlacion Genotipo / Fenotipo en pacientes europeos con AHC. 2013. IP. Alexis Arzimanoglou. Lyon J. Campistol , C. Fons , A. Ulate, L. Martorell Servei de Neurología Hospital San Joan de Déu Universitat de Barcelona