Precision Medicine: SCN8A Encephalopathy Treated with Sodium Channel Blockers

Møller, Rikke S.; Johannesen, Katrine M

doi:10.1007/s13311-015-0403-5

Cited by 40 publications

(41 citation statements)

References 13 publications

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“…Both patients had an SCN1A missense variant p.Gly177Glu and p.Leu942Val, which raises the question whether Dravet syndrome also can be caused by gain-of-function mutations as seen in EEs caused by other sodium channel genes, e.g., SCN2A and SCN8A [Kearney et al, 2001;Veeramah et al, 2012]. In the 2 patients harboring an SCN8A missense variant, we found, as previously reported [Wagnon and Meisler, 2015;Boerma et al, 2016;Møller and Johannesen, 2016], a good response to the SCB oxcarbazepine and a poor response to levetiracetam [Wagnon and Meisler, 2015]. The patient with the SCN8A nonsense mutation has been treated with lamotrigine, despite the fact that this variant is likely to cause a LOF loss of function of the channel.…”

Section: Discussionsupporting

confidence: 76%

Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies

Larsen²,

et al. 2016

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In recent years, several genes have been causally associated with epilepsy. However, making a genetic diagnosis in a patient can still be difficult, since extensive phenotypic and genetic heterogeneity has been observed in many monogenic epilepsies. This study aimed to analyze the genetic basis of a wide spectrum of epilepsies with age of onset spanning from the neonatal period to adulthood. A gene panel targeting 46 epilepsy genes was used on a cohort of 216 patients consecutively referred for panel testing. The patients had a range of different epilepsies from benign neonatal seizures to epileptic encephalopathies (EEs). Potentially causative variants were evaluated by literature and database searches, submitted to bioinformatic prediction algorithms, and validated by Sanger sequencing. If possible, parents were included for segregation analysis. We identified a presumed disease-causing variant in 49 (23%) of the 216 patients. The variants were found in 19 different genes including SCN1A, STXBP1, CDKL5, SCN2A, SCN8A, GABRA1, KCNA2, and STX1B. Patients with neonatal-onset epilepsies had the highest rate of positive findings (57%). The overall yield for patients with EEs was 32%, compared to 17% among patients with generalized epilepsies and 16% in patients with focal or multifocal epilepsies. By the use of a gene panel consisting of 46 epilepsy genes, we were able to find a disease-causing genetic variation in 23% of the analyzed patients. The highest yield was found among patients with neonatal-onset epilepsies and EEs.

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Section: Discussionsupporting

confidence: 76%

Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies

Larsen²,

et al. 2016

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“…[31, 32]. For benign familial infantile epilepsy caused by SCN8A mutation, seizures were easily controlled by mono-therapy.…”

Section: Discussionmentioning

confidence: 99%

“…While for the epileptic encephalopathy, seizures were not easy to control. Approximately half of patients showed good responses to sodium channel blockers, either as a reduction in seizures frequency or even seizure-free [31, 32]. Up to 1/3 of patients were seizure-free after treatment with antiepileptic drugs [9].…”

Section: Discussionmentioning

confidence: 99%

SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures

et al. 2017

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Background SCN8A mutations have recently been associated with epilepsy and neurodevelopmental disorders. This study aimed to broaden the phenotypic-spectrum of disease related with SCN8A mutations.MethodsTo identify the pathogenic gene of a Chinese family, in which six members suffered from epilepsy, whole-exome sequencing was performed. In addition, target next-generation sequencing (NGS) was performed on 178 sporadic patients, who had epilepsy of unknown etiology within 6 months after birth. A detailed clinical history was obtained.ResultsA heterozygous missense mutation of SCN8A was identified in the Chinese family. Six de novo mutations of SCN8A were detected in 6 sporadic patients with epilepsy. In the family, six members developed seizures within a few years after birth. Five of them had milder clinical performance, that they had normal cognition and developmental milestones, and seizure-free was achieved by mono-therapy. The other one affected member presented with refractory epilepsy and developmental regression. She died from sudden unexpected death in epilepsy (SUDEP) at 17-year-old. Clinical features of six sporadic patients with SCN8A mutations were diverse, ranging from severe epileptic encephalopathy to benign epilepsy with normal cognition. Seizures started at the mean age of 3.9 months (from 2 months to 6 months). Seizure-free was achieved in four of them by mono- or multi-antiepileptic drugs. Five of them demonstrated mild or severe psychomotor retardation, whereas the other one was normal in development and intelligence.ConclusionsOur findings extend the spectrum of SCN8A mutations and the clinical features of patients with SCN8A mutations. The majority of SCN8A mutations were de novo, inherited mutations from the heterozygous parents can also occur. The phenotypic spectrum of SCN8A mutation varied largely. Most affected patients manifested as refractory epilepsy and severe intellectual disability, only a small number of patients presented with milder clinical patterns. Additionally, our study confirmed that the same mutation can lead to different phenotypes.Electronic supplementary materialThe online version of this article (10.1186/s12881-017-0460-1) contains supplementary material, which is available to authorized users.

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“…Variants in SCN2A , encoding a third voltage‐gated sodium channel in the human central nervous system, can lead to both GOF and LOF, complicating things even more . Awareness of these important differences in pathophysiology is necessary, as it might have therapeutic implications …”

Section: Introductionmentioning

confidence: 99%

The spectrum of intermediate SCN8A‐related epilepsy

et al. 2019

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Summary Objective Pathogenic variants in SCN8A have been associated with a wide spectrum of epilepsy phenotypes, ranging from benign familial infantile seizures (BFIS) to epileptic encephalopathies with variable severity. Furthermore, a few patients with intellectual disability (ID) or movement disorders without epilepsy have been reported. The vast majority of the published SCN8A patients suffer from severe developmental and epileptic encephalopathy (DEE). In this study, we aimed to provide further insight on the spectrum of milder SCN8A‐related epilepsies. Methods A cohort of 1095 patients were screened using a next generation sequencing panel. Further patients were ascertained from a network of epilepsy genetics clinics. Patients with severe DEE and BFIS were excluded from the study. Results We found 36 probands who presented with an SCN8A‐related epilepsy and normal intellect (33%) or mild (61%) to moderate ID (6%). All patients presented with epilepsy between age 1.5 months and 7 years (mean = 13.6 months), and 58% of these became seizure‐free, two‐thirds on monotherapy. Neurological disturbances included ataxia (28%) and hypotonia (19%) as the most prominent features. Interictal electroencephalogram was normal in 41%. Several recurrent variants were observed, including Ile763Val, Val891Met, Gly1475Arg, Gly1483Lys, Phe1588Leu, Arg1617Gln, Ala1650Val/Thr, Arg1872Gln, and Asn1877Ser. Significance With this study, we explore the electroclinical features of an intermediate SCN8A‐related epilepsy with mild cognitive impairment, which is for the majority a treatable epilepsy.

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Precision Medicine: SCN8A Encephalopathy Treated with Sodium Channel Blockers

Cited by 40 publications

References 13 publications

Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies

Gene Panel Testing in Epileptic Encephalopathies and Familial Epilepsies

SCN8A mutations in Chinese patients with early onset epileptic encephalopathy and benign infantile seizures

The spectrum of intermediate SCN8A‐related epilepsy

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