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

Abstract

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.

Phenotypic and genetic spectrum of SCN8A‐related disorders, treatment options, and outcomes

“…Only one of them died of definite SUDEP, at the age of 15 years . Two additional young patients (17 and 19 years old) had a possible/probable SUDEP, and two children (26 months and 5 years old) died after prolonged seizures, suggesting a possible SUDEP . In total, five of 235 (2.1%) patients with pathogenic SCN8A mutations died of definite or possible SUDEP.…”

“…Recently, the same variant was also found in a Chinese family with a similar phenotype . A second pathogenic variant, Asn1877Ser, has been reported both in BFIS and in sporadic cases with drug‐responsive focal epilepsy (Tables and a) …”

The novel sodium channel modulator GS‐458967 (GS967) is an effective treatment in a mouse model of SCN8A encephalopathy

“…Targeting persistent sodium current, one of the common primary biophysical defects in this disorder, may provide an effective precision therapeutic approach. Reports have described patients achieving seizure control with carbamazepine, oxcarbazepine, valproic acid, and most notably, high‐dose phenytoin . Phenytoin is a state‐dependent sodium channel blocker with a small preference (~10%) for persistent current over peak current .…”

“…Reports have described patients achieving seizure control with carbamazepine, oxcarbazepine, valproic acid, and most notably, high-dose phenytoin. [11][12][13][14][15][16] Phenytoin is a state-dependent sodium channel blocker with a small preference (~10%) for persistent current over peak current. 17 However, high-dose phenytoin has significant safety concerns due to saturable metabolism and risk for phenytoin poisoning.…”

NaV1.1 and NaV1.6 selective compounds reduce the behavior phenotype in a novel zebrafish model for Dravet Syndrome

“…This disease mechanism is reflected by the therapeutic response of VGSC blockers. Various clinical reports have shown that SCN8A-related epilepsy patients benefit from VGSC blockers [9] [10] , contrasting their inefficacy, or even detrimental effects in DS [11] . These observations indicate that Na V 1.1 and Na V 1.6 represent two opposing sides of the neuronal balance between inhibition and activation.…”