SCN8A encephalopathy: Research progress and prospects

Abstract

On April 21, 2015, the first SCN8A Encephalopathy Research Group convened in Washington, DC, to assess current research into clinical and pathogenic features of the disorder and prepare an agenda for future research collaborations. The group comprised clinical and basic scientists and representatives of patient advocacy groups. SCN8A encephalopathy is a rare disorder caused by de novo missense mutations of the sodium channel gene SCN8A, which encodes the neuronal sodium channel Nav 1.6. Since the initial description in 2012, approximately 140 affected individuals have been reported in publications or by SCN8A family groups. As a result, an understanding of the severe impact of SCN8A mutations is beginning to emerge. Defining a genetic epilepsy syndrome goes beyond identification of molecular etiology. Topics discussed at this meeting included (1) comparison between mutations of SCN8A and the SCN1A mutations in Dravet syndrome, (2) biophysical properties of the Nav 1.6 channel, (3) electrophysiologic effects of patient mutations on channel properties, (4) cell and animal models of SCN8A encephalopathy, (5) drug screening strategies, (6) the phenotypic spectrum of SCN8A encephalopathy, and (7) efforts to develop a bioregistry. A panel discussion of gaps in bioregistry, biobanking, and clinical outcomes data was followed by a planning session for improved integration of clinical and basic science research. Although SCN8A encephalopathy was identified only recently, there has been rapid progress in functional analysis and phenotypic classification. The focus is now shifting from identification of the underlying molecular cause to the development of strategies for drug screening and prioritized patient care.

Keywords: Bioregistry; Drug screening; Encephalopathy; Mutation; Nav1.6; SCN8A; Sodium channel.

Figure 1

Locations of missense mutations in SCN8A encephalopathy. The Na_v1.6 channel encoded by SCN8A is composed of four homologous domains (DI to DIV), each containing six transmembrane segments (S1–S6). The channel also contains intracellular N-terminal and C-terminal domains, two large intracellular loops, and a small intracellular loop between domain III and domain IV, which functions as the inactivation gate. Thirty-one published de novo mutations that were identified in 50 unrelated patients are shown. Pathogenic mutations are concentrated in transmembrane segments and in the N- and C-terminal domains. Black symbols, one patient; blue symbols, recurrent mutations found in multiple patients (Adapted from Wagnon and Meisler). [Correction added after online publication on June 13, 2016: figure credit changed from Takahashi et al. to Wagnon and Meisler.]

Figure 2

Effects of gain-of-function mutations in SCN8A in patients with epileptic encephalopathy. (A) The Thr767Ile substitution in transmembrane segment S1 of domain II causes a hyperpolarizing shift in the voltage dependence of activation, resulting in premature channel opening. (B). Three mutations of Arg1872 in the cytoplasmic C-terminal domain remove a critical positive charge resulting in delayed channel inactivation. (C) The substitution Asn1768Asp in transmembrane segment S6 of domain IV results in an increase in persistent sodium current that facilitates repetitive firing. [Correction added after online publication on June 13, 2016: reference numbers updated for parts (A), (B), and (C) in the caption.]

Figure 3

A mouse model of SCN8A encephalopathy generated by knock-in of the patient mutation p.Asn1768Asp (N1768D). Approximately 45% of the heterozygous D/+ mice develop abnormal EEG findings and seizures leading to premature death before 6 months of age. Homozygous D/D mice and hemizygous D/− mice are more severely affected. The number of mice in each group is shown in parentheses (adapted from Wagnon et al.). [Correction added after online publication on June 13, 2016: figure credit changed from Takahashi et al. to Wagnon et al.]