Current Treatment Strategies and Future Treatment Options for Dravet Syndrome

Ziobro, Julie; Eschbach, Krista; Sullivan, Joseph; Knupp, Kelly G.

doi:10.1007/s11940-018-0537-y

Cited by 31 publications

(46 citation statements)

References 71 publications

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“…Correct and prompt diagnosis is critical, allowing the establishment of early treatment with appropriate anti-seizure medication, as well as aggressive rescue plans in episodes of status epilepticus [5]. To facilitate this, sequencing of the SCN1A gene is recommended in children with a clinical picture suggestive of Dravet syndrome [5, 27]. While the degree of Na V 1.1 loss of function is considered correlative with the severity of clinical phenotype [6, 26], prognosis in de novo missense SCN1A mutations generally awaits the presentation of developmental delay due to the challenges remaining in correctly foretelling the functional outcome of these mutations.…”

Section: Discussionmentioning

confidence: 99%

In vivo, in vitro and in silico correlations of four de novo SCN1A missense mutations

et al. 2019

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Mutations in the SCN1A gene, which encodes for the voltage-gated sodium channel NaV1.1, cause Dravet syndrome, a severe developmental and epileptic encephalopathy. Genetic testing of this gene is recommended early in life. However, predicting the outcome of de novo missense SCN1A mutations is difficult, since milder epileptic syndromes may also be associated. In this study, we correlated clinical severity with functional in vitro electrophysiological testing of channel activity and bioinformatics prediction of damaging mutational effects. Three patients, bearing the mutations p.Gly177Ala, p.Ser259Arg and p.Glu1923Arg, showed frequent intractable seizures that had started early in life, with cognitive and behavioral deterioration, consistent with classical Dravet phenotypes. These mutations failed to produce measurable sodium currents in a mammalian expression system, indicating complete loss of channel function. A fourth patient, who harbored the mutation p.Met1267Ile, though presenting with seizures early in life, showed lower seizure burden and higher cognitive function, matching borderland Dravet phenotypes. In correlation with this, functional analysis demonstrated the presence of sodium currents, but with partial loss of function. In contrast, six bioinformatics tools for predicting mutational pathogenicity suggested similar impact for all mutations. Likewise, homology modeling of the secondary and tertiary structures failed to reveal misfolding. In conclusion, functional studies using patch clamp are suggested as a prognostic tool, whereby detectable currents imply milder phenotypes and absence of currents indicate an unfavorable prognosis. Future development of automated patch clamp systems will facilitate the inclusion of such functional testing as part of personalized patient diagnostic schemes.

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Section: Discussionmentioning

confidence: 99%

In vivo, in vitro and in silico correlations of four de novo SCN1A missense mutations

et al. 2019

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“…Nevertheless, the approach of identifying the cause of a particular epilepsy and establishing a rational treatment option remains attractive and may offer a novel strategy for epilepsies that were previously resistant to treatment. Perhaps the best example of this is the understanding of disease biology and patterns of response to existing ASDs that has emerged from the now well-established finding that most cases of Dravet syndrome are due to loss-of-function pathogenic variants in SCN1A (Ziobro et al, 2018), though there is still a need for better treatments (Brigo et al, 2018;Mantegazza and Broccoli, 2019). Whether the paradigm that Dravet syndrome so nicely illustrates will be commonly replicated for other such defined epilepsies remains to be seen.…”

Section: B Precision Medicinementioning

confidence: 99%

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

et al. 2020

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Significance Statement-Drug resistance provides a major challenge in epilepsy management. Here, we will review the current understanding of the molecular, genetic, and structural mechanisms of drug resistance in epilepsy and discuss how the problem might be overcome. 608 Löscher et al. Adapted from Rogawski and Löscher (2004), Rogawski et al. (2016), and Sills and Rogawski (2020) Molecular target ASDs that act on target Voltage-gated ion channels Voltage-gated sodium channels Phenytoin, fosphenytoin, a carbamazepine, oxcarbazepine, b eslicarbazepine acetate, c lamotrigine, lacosamide; possibly topiramate, zonisamide, rufinamide Voltage-gated calcium channels (T-type) Ethosuximide Voltage-gated potassium channels (K v 7) Retigabine (ezogabine) GABA-mediated inhibition GABA A receptors Phenobarbital, primidone, stiripentol, benzodiazepines, (including diazepam, lorazepam, midazolam and clonazepam), possibly topiramate, felbamate, retigabine (ezogabine) GAT1 GABA transporter Tiagabine GABA transaminase Vigabatrin Glutamic acid decarboxylase Possibly valproate, gabapentin, pregabalin Presynaptic release machinery SV2A Levetiracetam, brivaracetam a2d subunit of calcium channels Gabapentin, pregabalin Ionotropic glutamate receptors AMPA receptor Perampanel Carbonic anhydratase inhibition Acetazolamide, topiramate, zonisamide, possibly lacosamide Disease-specific mTORC1 signaling d Everolimus Lysosomal enzyme replacement e Cerliponase alfa (recombinant tripeptidyl peptidase 1) Mixed/unknown Valproate, felbamate, topiramate, zonisamide, rufinamide, adrenocorticotrophin (ACTH), cannabidiol, cenobamate AMPA, a-amino-3-hydroxy-5-methyl-4-isoxazole-propionate. a Fosphenytoin is a prodrug for phenytoin. b Oxcarbazepine serves largely as a prodrug for licarbazepine, mainly S-licarbazepine. c Eslicarbarbazepine acetate is a prodrug for S-licarbazepine. d In patients with epilepsy because of tuberous sclerosis complex (TSC). e In patients with epilepsy because of neuronal ceroid lipofuscinosis type 2.

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“…Due to the role of the NaV1.1 channels in the regulation of electrical excitability by the inhibitory interneurons, prescription of AEDs non-selective sodium channel blockers (SCB) for SMEI or GEFS + syndromes is contraindicated, for it may aggravate crises due to the enhanced suppress status of the NaV1.1 channels (Catterall, 2014a;Shi et al, 2016;Knupp and Wirrell, 2018;Ziobro et al, 2018). The first-line drug-based therapy for SCN1A epilepsy diseases is the enhancement of postsynaptic GABAergic transmission with allosteric activation of GABA A receptors as target by Clobazam and/or an increase in GABA concentration in synaptic cleft resulting from increased GABA production and decreased GABA degradation as target by Valproic acid (Catterall, 2014a;Hammer et al, 2016;Knupp and Wirrell, 2018;Musto et al, 2020).…”

Section: Nav11mentioning

confidence: 99%

Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

et al. 2020

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Epilepsy is a disease characterized by abnormal brain activity and a predisposition to generate epileptic seizures, leading to neurobiological, cognitive, psychological, social, and economic impacts for the patient. There are several known causes for epilepsy; one of them is the malfunction of ion channels, resulting from mutations. Voltage-gated sodium channels (NaV) play an essential role in the generation and propagation of action potential, and malfunction caused by mutations can induce irregular neuronal activity. That said, several genetic variations in NaV channels have been described and associated with epilepsy. These mutations can affect channel kinetics, modifying channel activation, inactivation, recovery from inactivation, and/or the current window. Among the NaV subtypes related to epilepsy, NaV1.1 is doubtless the most relevant, with more than 1500 mutations described. Truncation and missense mutations are the most observed alterations. In addition, several studies have already related mutated NaV channels with the electrophysiological functioning of the channel, aiming to correlate with the epilepsy phenotype. The present review provides an overview of studies on epilepsy-associated mutated human NaV1.1, NaV1.2, NaV1.3, NaV1.6, and NaV1.7.

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Current Treatment Strategies and Future Treatment Options for Dravet Syndrome

Cited by 31 publications

References 71 publications

In vivo, in vitro and in silico correlations of four de novo SCN1A missense mutations

In vivo, in vitro and in silico correlations of four de novo SCN1A missense mutations

Drug Resistance in Epilepsy: Clinical Impact, Potential Mechanisms, and New Innovative Treatment Options

Epilepsy-Related Voltage-Gated Sodium Channelopathies: A Review

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