Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease

Muñoz‐Ballester, Carmen; Berthier, Arnaud; Viana, Rosa; Sanz, Pascual

doi:10.1016/j.bbadis.2016.03.008

Cited by 29 publications

(26 citation statements)

References 41 publications

(64 reference statements)

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“…One recent study suggested that there is preferential loss of GABAergic inhibitory interneurons 15 . Another reported that astrocytic glutamate clearance is impaired 16 , and there are yet other working hypotheses. In any case, perampanel would likely confer benefit by diminishing neuronal network hyper-excitability at least in part through its known AMPA antagonism.…”

Section: Discussionmentioning

confidence: 99%

Efficacy and tolerability of perampanel in ten patients with Lafora disease

Goldsmith

Minassian

2016

Epilepsy & Behavior

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Summary Lafora disease (LD) is a fatal intractable adolescence-onset progressive myoclonus epilepsy. Recently, two single-case studies reported drastic reductions in seizures and myoclonus with the AMPA antagonist perampanel, and improved activities of daily living. We proceeded to study the effect of perampanel on10 genetically confirmed LD patients with disease duration ranging from 2 to 27 years. Open-labeled perampanel was added to ongoing medications to a mean dose of 6.7 mg/day. Seizures, myoclonus, functional disability and cognition scores were measured for the third and ninth month following initiation and compared to the month prior to start of therapy. Three patients withdrew due to inefficacy or side-effects. Four had significant reduction in seizures of greater than 74% from baseline. Seven had major improvement in myoclonus with group-adjusted sum score of myoclonus intensity reduced from 7.01 at baseline to 5.67 and 5.18 at 3 and 9 months respectively. There was no significant improvement in disability and cognition. While not universal, perampanel adjunctive therapy appears to confer particular benefit not commonly seen with other anti-epileptic drugs on seizures and myoclonus in LD. Improvement in the extremely disabling myoclonus of LD is a major benefit in this devastating disease.

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Section: Discussionmentioning

confidence: 99%

Efficacy and tolerability of perampanel in ten patients with Lafora disease

Goldsmith

Minassian

2016

Epilepsy & Behavior

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“…In fact, studies on the mouse model of this disease have indicated a disruption in the homeostasis of the glutamate transporter GLT‐1 (EAAT2), resulting in reduced capacity of glutamate transport. This is consistent with the anti‐seizure mechanisms of action of VNS which include, as mentioned above, anti‐glutamatergic effects (Muñoz‐Ballester et al ., ).…”

Section: Discussionmentioning

confidence: 99%

Managing Lafora body disease with vagal nerve stimulation

Mikati

Tabbara

2017

Epileptic Disorders

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A 17‐year‐old female, of consanguineous parents, presented with a history of seizures and cognitive decline since the age of 12 years. She had absence, focal dyscognitive, generalized myoclonic, and generalized tonic‐clonic seizures, all of which were drug resistant. The diagnosis of Lafora body disease was made based on a compatible clinical, EEG, seizure semiology picture and a disease‐causing homozygous mutation in the EPM2A gene. A vagus nerve stimulator (VNS) was inserted and well tolerated with a steady decrease and then stabilization in seizure frequency during the six months following insertion (months 1–6). At follow‐up, at 12 months after VNS insertion, there was a persistent improvement. Seizure frequency during months 7–12, compared to pre‐VNS, was documented as follows: the absence seizures observed by the family had decreased from four episodes per month to 0 per month, the focal dyscognitive seizures from 300 episodes per month to 90 per month, the generalized myoclonic seizures from 90 clusters per month to eight per month, and the generalized tonic‐clonic seizures from 30 episodes per month to 1.5 per month on average. To our knowledge, this is the second case reported in the literature showing efficacy of VNS in the management of seizures in Lafora body disease.

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“…Por otro lado, se ha visto que la homeostasis del transportador del glutamato GLT-1, denominado EAAT2 en humanos y responsable de la recaptación del 90% del glutamato en el sistema nervioso central, se ve comprometida en ratones Epm2a -/y Epm2b -/-, observándose niveles disminuidos en la membrana plasmática de los astrocitos. Esto podría asociarse a la hiperexcitabilidad y la muerte neuronal que se produce en la LD [56]. Asimismo, se ha visto un incremento del número de astrocitos reactivos y microglía en ratones modelo de la enfermedad de ambos genes, así como un incremento de la expresión de genes que codifican citoquinas y mediadores de la respuesta inflamatoria [57].…”

Section: Nuevas Perspectivas Más Allá Del Metabolismo Del Glucógenounclassified

Enfermedad de Lafora: revisión de la bibliografía

Desdentado

Espert

Sanz³

et al. 2019

RevNeurol

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Este trabajo no ha sido financiado por ninguna entidad. Conflictos de interésNo existen conflictos de interés Resumen.Introducción. La enfermedad de Lafora (LD) es una forma de epilepsia mioclónica progresiva de herencia autosómica recesiva, de inicio en la infancia tardía o en la adolescencia, y producida por mutaciones de pérdida de función en los genes EPM2A o EPM2B, los cuales codifican para las proteínas laforina y malina, respectivamente.Desarrollo. Los principales síntomas de la enfermedad, que empeoran progresivamente, son: mioclonías, crisis occipitales, crisis tónico-clónicas generalizadas, deterioro cognitivo, síntomas neuropsiquiátricos, y ataxia. El curso es progresivo y fatal. Patológicamente, la LD se caracteriza por la presencia de depósitos de poliglucosanos llamados cuerpos de Lafora (LBs, del inglés Lafora bodies) en el cerebro, hígado, músculo, y glándulas sudoríparas. El diagnóstico de LD se realiza mediante hallazgos clínicos, electrofisiológicos, histológicos y genéticos. Actualmente, no existe un tratamiento que erradique o prevenga el desarrollo de la enfermedad. Tradicionalmente, se utilizan fármacos antiepilépticos para el manejo de las mioclonías y las convulsiones, aunque aparecen resistencias a los mismos.Conclusiones. La LD es una enfermedad rara que, pese a su baja prevalencia, supone graves consecuencias para los pacientes y sus cuidadores. Así pues, resulta necesario continuar la investigación para clarificar los mecanismos subyacentes y desarrollar nuevos tratamientos paliativos y curativos de la enfermedad.

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Homeostasis of the astrocytic glutamate transporter GLT-1 is altered in mouse models of Lafora disease

Cited by 29 publications

References 41 publications

Efficacy and tolerability of perampanel in ten patients with Lafora disease

Efficacy and tolerability of perampanel in ten patients with Lafora disease

Managing Lafora body disease with vagal nerve stimulation

Enfermedad de Lafora: revisión de la bibliografía

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