Focal epilepsy in <i>SCN1A</i>‐mutation carrying patients: is there a role for epilepsy surgery?

Vezyroglou, Katharina; Varadkar, Sophia; Bast, Thomas; Hirsch, Édouard; Strobl, Karl; Harvey, A. Simon; Scheffer, Ingrid E.; Sisodiya, Sanjay M.; Cross, J. Helen

doi:10.1111/dmcn.14588

Cited by 24 publications

(25 citation statements)

References 23 publications

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“…However, SCN1A gene variants are also a recognized cause for epilepsies and neurodevelopmental disorders outside the Dravet syndrome spectrum—ranging from milder phenotypes such as generalized epilepsy with febrile seizures plus ( Escayg et al, 2000 ), to other epilepsy syndromes such as myoclonic astatic epilepsy, epilepsy of infancy with migrating focal seizures, or even to recently described more severe early onset epileptic encephalopathies with neurodegeneration and dyskinesia ( Sadleir et al, 2017 ; Beck et al, 2019 ; Gorman et al, 2021 ). With increased genetic testing, SCN1A variants have been described in patients with focal epilepsies ( Vezyroglou et al, 2020 )—both in patients that were candidates for epilepsy surgery, and those with self-limiting focal epilepsies of childhood. These patients are part of a minority of cases of focal epilepsy for which single gene causes have been identified.…”

Section: Introductionmentioning

confidence: 99%

The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function

et al. 2021

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Variants of the SCN1A gene encoding the neuronal voltage-gated sodium channel NaV1.1 cause over 85% of all cases of Dravet syndrome, a severe and often pharmacoresistent epileptic encephalopathy with mostly infantile onset. But with the increased availability of genetic testing for patients with epilepsy, variants in SCN1A have now also been described in a range of other epilepsy phenotypes. The vast majority of these epilepsy-associated variants are de novo, and most are either nonsense variants that truncate the channel or missense variants that are presumed to cause loss of channel function. However, biophysical analysis has revealed a significant subset of missense mutations that result in increased excitability, further complicating approaches to precision pharmacotherapy for patients with SCN1A variants and epilepsy. We describe clinical and biophysical data of a familial SCN1A variant encoding the NaV1.1 L1624Q mutant. This substitution is located on the extracellular linker between S3 and S4 of Domain IV of NaV1.1 and is a rare case of a familial SCN1A variant causing an autosomal dominant frontal lobe epilepsy. We expressed wild-type (WT) and L1642Q channels in CHO cells. Using patch-clamp to characterize channel properties at several temperatures, we show that the L1624Q variant increases persistent current, accelerates fast inactivation onset and decreases current density. While SCN1A-associated epilepsy is typically considered a loss-of-function disease, our results put L1624Q into a growing set of mixed gain and loss-of-function variants in SCN1A responsible for epilepsy.

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Section: Introductionmentioning

confidence: 99%

The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function

et al. 2021

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“…24 In SCN1A epilepsy, sodium channel blockers should be avoided, epilepsy surgery should probably not be pursued unless the phenotype is mild, and a potential use of cannabidiol, stiripentol, fenfluramine, and clemizole in the treatment of this condition is under investigation. [25][26][27][28] In MELAS syndrome, multidisciplinary care is crucial, and valproic acid as well as many other ASMs should be avoided due to concerns of mitochondrial toxicity. 29 Whereas in McKnight et al's study 55.5% of genetic diagnoses were clinically actionable, in our study, 71% of diagnoses were clinically actionable.…”

Section: Discussionmentioning

confidence: 99%

Usage of Genetic Panels in an Adult Epilepsy Clinic

Toffa

Lefèbvre

et al. 2022

Can. J. Neurol. Sci.

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Background: There is limited data on the utility, yield, and cost efficiency of genetic testing in adults with epilepsy. We aimed to describe the yield and utility of genetic panels in our adult epilepsy clinic. Methods: We performed a retrospective, cross-sectional study of all patients followed by an epileptologist at a Canadian tertiary care centre’s epilepsy clinic between January 2016 and August 2021 for whom a genetic panel was ordered. A panel was generally ordered when the etiology was unknown or in the presence of a malformation of cortical development. We determined the yield of panel positivity and of confirmed genetic diagnoses. We also estimated the proportion of these diagnoses that were clinically actionable. Results: In total, 164 panels were ordered in 164 patients. Most had refractory epilepsy (80%), and few had comorbid intellectual disability (10%) or a positive family history of epilepsy (11%). The yield of panel positivity was 11%. Panel results were uncertain 49% of the time and negative 40% of the time. Genetic diagnoses were confirmed in 7 (4.3%) patients. These genetic conditions involved the following genes: SCARB2, DEPDC5, PCDH19, LGI1, SCN1A, MT-TL1, and CHRNA7. Of the seven genetic diagnoses, 5 (71%) were evaluated to be clinically actionable. Conclusion: We report a lower diagnostic yield for genetic panels in adults with epilepsy than what has so far been reported. Although the field of the genetics of epilepsy is a fast-moving one and more data is required, our findings suggest that guidelines for genetic testing in adults are warranted.

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“…These measures were unavailable at the time the proband was seen. Functional testing of the variant in vitro showed loss‐of‐function (B; Ref 69…”

Section: Precision Medicine and The Pivot Of Geneticsmentioning

confidence: 99%

“…Functional testing of the variant in vitro showed loss‐of‐function (B; Ref. 69 ). At this point, the full pedigree (C, blue rectangle) became available through the proband's maternal grandmother.…”

Section: Precision Medicine and The Pivot Of Geneticsmentioning

confidence: 99%

Precision medicine and therapies of the future

Sisodiya

2020

Epilepsia

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Precision medicine in the epilepsies has gathered much attention, especially with gene discovery pushing forward new understanding of disease biology. Several targeted treatments are emerging, some with considerable sophistication and individual‐level tailoring. There have been rare achievements in improving short‐term outcomes in a few very select patients with epilepsy. The prospects for further targeted, repurposed, or novel treatments seem promising. Along with much‐needed success, difficulties are also arising. Precision treatments do not always work, and sometimes are inaccessible or do not yet exist. Failures of precision medicine may not find their way to broader scrutiny. Precision medicine is not a new concept: It has been boosted by genetics and is often focused on genetically determined epilepsies, typically considered to be driven in an individual by a single genetic variant. Often the mechanisms generating the full clinical phenotype from such a perceived single cause are incompletely understood. The impact of additional genetic variation and other factors that might influence the clinical presentation represent complexities that are not usually considered. Precision success and precision failure are usually equally incompletely explained. There is a need for more comprehensive evaluation and a more rigorous framework, bringing together information that is both necessary and sufficient to explain clinical presentation and clinical responses to precision treatment in a precision approach that considers the full picture not only of the effects of a single variant, but also of its genomic and other measurable environment, within the context of the whole person. As we may be on the brink of a treatment revolution, progress must be considered and reasoned: One possible framework is proposed for the evaluation of precision treatments.

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Focal epilepsy in SCN1A‐mutation carrying patients: is there a role for epilepsy surgery?

Cited by 24 publications

References 23 publications

The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function

The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function

Usage of Genetic Panels in an Adult Epilepsy Clinic

Precision medicine and therapies of the future

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