The Effect of Scn1A Mutations on Patient-Derived Gabaergic Neurons: What Are the Implications For Future Dravet Syndrome Therapeutics?

Abstract

part of Epilepsy is a common neurological disease affecting 0.5–1% of the general population that occurs in various conditions, in which recurrent ‘epileptic seizures’ are induced. Currently, 20–30% of patients have seizures that are not well controlled by available treatments. Dravet syndrome (DS) is one of these intractable epilepsies, and is characterized by infantile-onset seizures and severe intellectual disability [1]. The disease was named after Charlotte Dravet who first described this condition in 1978. Although rare (the incidence is one in 20,000–40,000), DS has been a focus point in epilepsy research since a robust relationship between the clinical phenotype and genetic cause has been established. In DS, initial seizures occur in the form of generalized or unilateral convulsive seizures that are frequently associated with fever or simply an elevation in body temperature (e.g., hot-water bathing) [1]. The seizures tend to be prolonged, frequently evolving into status epilepticus, particularly when no therapeutic intervention is made. Other types of seizures, including focal, absence and myoclonic, appear subsequently. Although initially normal, psychomotor development stagnates after seizure onset, and it is often accompanied by hyperactive behaviors and autistic traits. Generalized convulsions and severe cognitive decline persist over the course of patients’ lives. Ataxia also progresses with age and leads to gait disturbance. Unexpected death at a young age is another critical issue, and 10–20% of the afflicted children die prematurely [2]. Currently, treating DS remains a challenge. Although stiripentol, topiramate and potassium bromide may show efficacy for suppressing seizures, many patients remain epileptic and suffer developmental stagnation [3]. However, despite its progressive nature, DS may be a curable disease. Psychomotor milestones are normal before seizure onset; some patients who attained good initial seizure control showed excellent seizure and intellectual outcomes [4]; and neuronal death was not accelerated in the autopsy of brain specimens of adult patients [5]. These findings strongly imply that early interventions with some new and improved treatments could significantly improve the prognosis of DS. Genetic defects in SCN1A, which encodes the a1-subunit of the voltage-gated sodium channel Na V 1.1, were revealed as a primary cause of DS in 2001 [6]. This has significantly accelerated research into this condition, more specifically by using murine DS models, as well as our understanding of DS pathogenesis [7,8]. It is currently known that many DS mutations in SCN1A cause a significant deterioration in Na V 1.1 function (i.e., producing a nonfunctional channel) [9]; haploinsufficiency of this channel may be the primary mechanism [10]. A functional decline in the GABAergic interneurons, where Na V 1.1 is primarily expressed in the mouse neocortex and The effect of SCN1A mutations on patient-derived GABAergic neurons: what are the implications for future Dravet syndrome therapeutics?