Novedades en la Hemiplejia Alternante de la Infancia

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