Antiepileptic drugs in Rett Syndrome

Pintaudi, Maria; Calevo, Maria Grazia; Baglietto, M. G.; Hayek, Joussef; Traverso, Maria Esther Duran; Giacomini, Thea; Giordano, Lucio; Renieri, Alessandra; Russo, Silvia; Canevini, Maria Paola; Veneselli, Edvige

doi:10.1016/j.ejpn.2015.02.007

Cited by 15 publications

(17 citation statements)

References 36 publications

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“…Seizures of various semiology were described, with the most common being generalized seizures, tonic-clonic seizures and complex partial seizures [ 41 , 42 , 43 , 44 , 45 ]. Reports on the prevalence of epilepsy in patients with RTT ranged between 50 and 90%, and about 30–50% of cases were drug-resistant [ 41 , 44 , 46 , 47 , 48 , 49 , 50 , 51 , 52 , 53 ]. This wide range of results might be related to different methods used to identify seizures.…”

Section: Resultsmentioning

confidence: 99%

Reviewing Evidence for the Relationship of EEG Abnormalities and RTT Phenotype Paralleled by Insights from Animal Studies

Smirnov

Stroganova²,

Molholm

et al. 2021

IJMS

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Rett syndrome (RTT) is a rare neurodevelopmental disorder that is usually caused by mutations of the MECP2 gene. Patients with RTT suffer from severe deficits in motor, perceptual and cognitive domains. Electroencephalogram (EEG) has provided useful information to clinicians and scientists, from the very first descriptions of RTT, and yet no reliable neurophysiological biomarkers related to the pathophysiology of the disorder or symptom severity have been identified to date. To identify consistently observed and potentially informative EEG characteristics of RTT pathophysiology, and ascertain areas most worthy of further systematic investigation, here we review the literature for EEG abnormalities reported in patients with RTT and in its disease models. While pointing to some promising potential EEG biomarkers of RTT, our review identify areas of need to realize the potential of EEG including (1) quantitative investigation of promising clinical-EEG observations in RTT, e.g., shift of mu rhythm frequency and EEG during sleep; (2) closer alignment of approaches between patients with RTT and its animal models to strengthen the translational significance of the work (e.g., EEG measurements and behavioral states); (3) establishment of large-scale consortium research, to provide adequate Ns to investigate age and genotype effects.

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Section: Resultsmentioning

confidence: 99%

Reviewing Evidence for the Relationship of EEG Abnormalities and RTT Phenotype Paralleled by Insights from Animal Studies

Smirnov

Stroganova²,

Molholm

et al. 2021

IJMS

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“…Additionally, this study does not address physician prescribing practices or the efficacy of specific anti-seizure medications. Based on previous publications, medication use is largely based on regional prescribing practices rather than efficacy or adverse effects (Bao et al, 2013;Pintaudi et al, 2015). Although cases and retrospective studies document efficacy of specific medications in Rett syndrome, no systematic study has demonstrated superiority of a specific medication or class of medications to treat epilepsy in Rett syndrome (Haas et al, 1986;Kumandas et al, 2001;Goyal et al, 2004;Specchio et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Longitudinal course of epilepsy in Rett syndrome and related disorders

Tarquinio

Hou

Berg

et al. 2016

Brain

100

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Epilepsy is common in Rett syndrome, an X-linked dominant disorder caused by mutations in the MECP2 gene, and in Rett-related disorders, such as MECP2 duplication. However, neither the longitudinal course of epilepsy nor the patterns of seizure onset and remission have been described in Rett syndrome and related conditions. The present study summarizes the findings of the Rett syndrome Natural History study. Participants with clinical Rett syndrome and those with MECP2 mutations without the clinical syndrome were recruited through the Rett Natural History study from 2006 to 2015. Clinical details were collected, and cumulative lifetime prevalence of epilepsy was determined using the Kaplan-Meier estimator. Risk factors for epilepsy were assessed using Cox proportional hazards models. Of 1205 participants enrolled in the study, 922 had classic Rett syndrome, and 778 of these were followed longitudinally for 3939 person-years. The diagnosis of atypical Rett syndrome with a severe clinical phenotype was associated with higher prevalence of epilepsy than those with classic Rett syndrome. While point prevalence of active seizures ranged from 30% to 44%, the estimated cumulative lifetime prevalence of epilepsy using Kaplan-Meier approached 90%. Specific MECP2 mutations were not significantly associated with either seizure prevalence or seizure severity. In contrast, many clinical features were associated with seizure prevalence; frequency of hospitalizations, inability to walk, bradykinesia, scoliosis, gastrostomy feeding, age of seizure onset, and late age of diagnosis were independently associated with higher odds of an individual having epilepsy. Aggressive behaviour was associated with lower odds. Three distinct patterns of seizure prevalence emerged in classic Rett syndrome, including those who did not have seizures throughout the study, those who had frequent relapse and remission, and those who had relentless seizures. Although 248 of those with classic Rett syndrome and a history of seizures were in terminal remission at last contact, only 74 (12% of those with a history of epilepsy) were seizure free and off anti-seizure medication. When studied longitudinally, point prevalence of active seizures is relatively low in Rett syndrome, although lifetime risk of epilepsy is higher than previously reported. While daily seizures are uncommon in Rett syndrome, prolonged remission is less common than in other causes of childhood onset epilepsy. Complete remission off anti-seizure medications is possible, but future efforts should be directed at determining what factors predict when withdrawal of medications in those who are seizure free is propitious.

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“…The increased amount of the inhibitory neurotransmitter γ-aminobutyric acid (GABA) in the brain is one of the proposed effects of VPA treatment, and inhibition of histone deacetylases (HDACs) by VPA is responsible for the mechanism [17]. Epilepsy affects approximately 80% of RTT patients [18], and VPA has been used most commonly for the treatment of epilepsy in RTT [19]. VPA has a rapid onset of action, but a marked increase in anticonvulsant activity is observed during prolonged treatment [16], which supports the hypothesis that epigenetic mechanisms underlie the pharmacological effect of VPA [17,20].…”

Section: Introductionmentioning

confidence: 99%

Early Postnatal Treatment with Valproate Induces Gad1 Promoter Remodeling in the Brain and Reduces Apnea Episodes in Mecp2-Null Mice

Ishiyama

Tamura

Ito

et al. 2019

IJMS

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The deletion of Mecp2, the gene encoding methyl-CpG-binding protein 2, causes severe breathing defects and developmental anomalies in mammals. In Mecp2-null mice, impaired GABAergic neurotransmission is demonstrated at the early stage of life. GABAergic dysfunction in neurons in the rostral ventrolateral medulla (RVLM) is considered as a primary cause of breathing abnormality in Mecp2-null mice, but its molecular mechanism is unclear. Here, we report that mRNA expression levels of Gad1, which encodes glutamate decarboxylase 67 (GAD67), in the RVLM of Mecp2-null (Mecp2-/y, B6.129P2(C)-Mecp2tm1.1Bird/J) mice is closely related to the methylation status of its promoter, and valproate (VPA) can upregulate transcription from Gad1 through epigenetic mechanisms. The administration of VPA (300 mg/kg/day) together with L-carnitine (30 mg/kg/day) from day 8 to day 14 after birth increased Gad1 mRNA expression in the RVLM and reduced apnea counts in Mecp2-/y mice on postnatal day 15. Cytosine methylation levels in the Gad1 promoter were higher in the RVLM of Mecp2-/y mice compared to wild-type mice born to C57BL/6J females, while VPA treatment decreased the methylation levels in Mecp2-/y mice. Chromatin immunoprecipitation assay revealed that the VPA treatment reduced the binding of methyl-CpG binding domain protein 1 (MBD1) to the Gad1 promoter in Mecp2-/y mice. These results suggest that VPA improves breathing of Mecp2-/y mice by reducing the Gad1 promoter methylation, which potentially leads to the enhancement of GABAergic neurotransmission in the RVLM.

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Antiepileptic drugs in Rett Syndrome

Cited by 15 publications

References 36 publications

Reviewing Evidence for the Relationship of EEG Abnormalities and RTT Phenotype Paralleled by Insights from Animal Studies

Reviewing Evidence for the Relationship of EEG Abnormalities and RTT Phenotype Paralleled by Insights from Animal Studies

Longitudinal course of epilepsy in Rett syndrome and related disorders

Early Postnatal Treatment with Valproate Induces Gad1 Promoter Remodeling in the Brain and Reduces Apnea Episodes in Mecp2-Null Mice

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