Changing Landscape of Dravet Syndrome Management: An Overview

Samanta, Debopam

doi:10.1055/s-0040-1701694

Cited by 26 publications

(24 citation statements)

References 59 publications

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“…In DS or “severe myoclonic epilepsy of infancy”, healthy children typically develop seizures between the age of five to eight months [ 7 , 62 , 63 ]. Seizures may be triggered by fever, vaccination, stress, and bathing.…”

Section: Developmental and Epileptic Encephalopathies (Dees)mentioning

confidence: 99%

“…Seizures may be triggered by fever, vaccination, stress, and bathing. Children experience prolonged hemiconvulsive or generalized febrile seizures during the first year of life [ 62 , 63 ]. This is followed by multiple types of intractable afebrile seizures, frequent occurrence of status epilepticus, and psychomotor retardation [ 63 ].…”

Section: Developmental and Epileptic Encephalopathies (Dees)mentioning

confidence: 99%

“…The most frequent SCN1A -related disorder is DS, and SCN1A -deficiency is also by far the most common genetic cause of DS [ 64 ]. In SCN1A- related DS, sodium channel blockers such as lamotrigine and carbamazepine should be avoided as they may aggravate seizures, while fenfluramine, cannabidiol, valproic acid, topiramate, clobazam, and stiripentol can be beneficial [ 62 , 83 ].…”

Section: Utility Of Early Genetic Testing For Precision Therapy Approachesmentioning

confidence: 99%

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Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy

Bayat

Rubboli

et al. 2021

Genes

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The high pace of gene discovery has resulted in thrilling advances in the field of epilepsy genetics. Clinical testing with comprehensive gene panels, exomes, or genomes are now increasingly available and have led to a significant higher diagnostic yield in early-onset epilepsies and enabled precision medicine approaches. These have been instrumental in providing insights into the pathophysiology of both early-onset benign and self-limited syndromes and devastating developmental and epileptic encephalopathies (DEEs). Genetic heterogeneity is seen in many epilepsy syndromes such as West syndrome and epilepsy of infancy with migrating focal seizures (EIMFS), indicating that two or more genetic loci produce the same or similar phenotypes. At the same time, some genes such as SCN2A can be associated with a wide range of epilepsy syndromes ranging from self-limited familial neonatal epilepsy at the mild end to Ohtahara syndrome, EIFMS, West syndrome, Lennox–Gastaut syndrome, or unclassifiable DEEs at the severe end of the spectrum. The aim of this study was to review the clinical and genetic heterogeneity associated with epilepsy syndromes starting in the first year of life including: Self-limited familial neonatal, neonatal-infantile or infantile epilepsies, genetic epilepsy with febrile seizures plus spectrum, myoclonic epilepsy in infancy, Ohtahara syndrome, early myoclonic encephalopathy, West syndrome, Dravet syndrome, EIMFS, and unclassifiable DEEs. We also elaborate on the advantages and pitfalls of genetic testing in such conditions. Finally, we describe how a genetic diagnosis can potentially enable precision therapy in monogenic epilepsies and emphasize that early genetic testing is a cornerstone for such therapeutic strategies.

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Section: Developmental and Epileptic Encephalopathies (Dees)mentioning

confidence: 99%

Section: Developmental and Epileptic Encephalopathies (Dees)mentioning

confidence: 99%

Section: Utility Of Early Genetic Testing For Precision Therapy Approachesmentioning

confidence: 99%

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Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy

Bayat

Rubboli

et al. 2021

Genes

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“…A highly purified form of pharmaceutical CBD has been approved for drug-resistant seizures associated with Dravet syndrome and Lennox-Gastaut syndrome [50,51]. Open-label trials of a pharmaceutical-grade CBD and other artisanal CBD products have shown long-term efficacy and safety of CBD in various other treatment-resistant epilepsy such as tuberous sclerosis, CDKL5 deficiency disorders, Aicardi syndrome, 15q duplication, and Doose syndrome.…”

Section: Cannabidiol (Cbd)mentioning

confidence: 99%

Epilepsy in Angelman syndrome: A scoping review

Samanta

2021

Brain and Development

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Angelman Syndrome (AS) is characterized by severe developmental delays including marked speech impairment, movement abnormalities(ataxia, tremor), and unique behaviors such as frequent laughter and is caused by dysfunctional maternal UBE3A gene (maternal 15q11-13 deletions, maternal specific UBE3A mutation, uniparental disomy, and imprinting defect). Intractable epileptic seizures since early childhood with characteristic EEG abnormalities are present in 80-90% patients with AS. Underlying pathophysiology may involve neocortical and thalamocortical hyperexcitability secondary to severe reduction of GABAergic input, as well as dysfunctional synaptic plasticity, deficient synaptogenesis, and neuronal morphological immaturity. The onset of epilepsy is most prevalent between 1 and 3 years of age; however, approximately 25% of patients developed epilepsy before one year of age. Various types of generalized seizures are most prevalent, with most common types are myoclonic and atypical absence. More than 95% of epilepsy patients may have daily seizures at least for a limited time during early childhood, and two-third patients develop disabling seizures. Fever provoked seizures, and frequent occurrence of nonconvulsive status epilepticus are two unique features. Seizures are frequently pharmacoresistant. Considering underlying prominent GABAergic dysfunction, clinicians had used AEDs that target GABAergic signaling such as valproate, phenobarbital, and clonazepam as first-line therapies for AS. However, due to the unfavorable side effect profile of these AEDs, a recent treatment approach involves priority use of levetiracetam, clobazam, topiramate, lamotrigine, ethosuximide, VNS, and carbohydrate-restricted diets. Besides symptomatic management, there has been recent progress to find a curative treatment with the following approaches: 1. Gene/protein replacement therapy (Adeno and lentiviral vector therapy to deliver a gene or secretory protein); 2. Activation of the intact but silent paternal copy of UBE3A (antisense oligonucleotide therapy and artificial transcription factors); and 3. Downstream therapies (OV101/gaboxadol, ketone supplement, novel compounds/peptides, anti-inflammatory/regenerative therapy).

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“…The resulting excitation/inhibition imbalance leads to network hyperexcitation and epileptic seizures, as well as other manifestations of DS ( Scheffer and Nabbout, 2019 ). Small-molecule and device-based treatments for DS, approved and under clinical development, were reviewed recently ( Samanta, 2020 ). As SCN1A mutations are not known to produce toxic protein, upregulation of the remaining healthy SCN1A allele represents a desirable therapeutic target in DS.…”

Section: Nbts In Orphan Neurological Disordersmentioning

confidence: 99%

Nucleic Acid–Based Therapeutics in Orphan Neurological Disorders: Recent Developments

Khorkova

Hsiao

Wahlestedt

2021

Front. Mol. Biosci.

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The possibility of rational design and the resulting faster and more cost-efficient development cycles of nucleic acid–based therapeutics (NBTs), such as antisense oligonucleotides, siRNAs, and gene therapy vectors, have fueled increased activity in developing therapies for orphan diseases. Despite the difficulty of delivering NBTs beyond the blood–brain barrier, neurological diseases are significantly represented among the first targets for NBTs. As orphan disease NBTs are now entering the clinical stage, substantial efforts are required to develop the scientific background and infrastructure for NBT design and mechanistic studies, genetic testing, understanding natural history of orphan disorders, data sharing, NBT manufacturing, and regulatory support. The outcomes of these efforts will also benefit patients with “common” diseases by improving diagnostics, developing the widely applicable NBT technology platforms, and promoting deeper understanding of biological mechanisms that underlie disease pathogenesis. Furthermore, with successes in genetic research, a growing proportion of “common” disease cases can now be attributed to mutations in particular genes, essentially extending the orphan disease field. Together, the developments occurring in orphan diseases are building the foundation for the future of personalized medicine. In this review, we will focus on recent achievements in developing therapies for orphan neurological disorders.

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Changing Landscape of Dravet Syndrome Management: An Overview

Cited by 26 publications

References 59 publications

Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy

Epilepsy Syndromes in the First Year of Life and Usefulness of Genetic Testing for Precision Therapy

Epilepsy in Angelman syndrome: A scoping review

Nucleic Acid–Based Therapeutics in Orphan Neurological Disorders: Recent Developments

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