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 Nav1.6. 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 Nav1.6 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.

Neuronal hyperexcitability in a mouse model of SCN8A epileptic encephalopathy

“…The activity of both excitatory and inhibitory neurons is reduced in mutant mice lacking Na v 1.6, and repetitive firing of cerebellar Purkinje cells and other repetitively firing neurons is impaired (1,(4)(5)(6)(7). De novo mutations of SCN8A have been identified as an important cause of early infantile epileptic encephalopathy (EIEE) (8,9). Epileptic encephalopathy resulting from mutation of SCN8A is designated EIEE13 [Online Mendelian Inheritance in Man (OMIM) # 614558].…”

“…Comorbidities included intellectual disability, ataxia, and sudden unexpected death in epilepsy (SUDEP) at 15 y of age. Since then, more than 150 patients with de novo SCN8A mutations have been identified (8,11) (www.scn8a. net/Home.aspx).…”

SCN8A mutation in a child presenting with seizures and developmental delays

“…In two cases, a hyperpolarizing shift in voltage dependence of channel activation was observed, also leading to hyperactivity. This gain-of-function mechanism is opposite to the situation in Dravet syndrome, where loss-of-function mutations in SCN1A are most common (Meisler et al 2016). …”

“…Approximately 1% of early infantile epileptic encephalopathies are associated with missense mutations in the SCN8A gene, and approximately 50 cases have been described in the literature (Veeramah et al 2012; Larsen et al 2015; Wagnon and Meisler 2015; Meisler et al 2016). In a few cases, the mutation was inherited from a mosaic parent, but the majority of disease-contributory mutations are de novo missense mutations (Wagnon and Meisler 2015).…”

“…EIEE13 has an average age of onset between 3 and 7 mo, and individuals present with various types of seizures, including tonic–clonic, generalized tonic, atonic, myoclonic, and focal and absence seizures, whereas febrile seizures are rare (Ohba et al 2014). There is often developmental regression, and movement disorders are present with 50% of affected individuals unable to sit or walk (Meisler et al 2016). …”