Interneuron, interrupted: molecular pathogenesis of ARX mutations and X-linked infantile spasms

Abstract

X-linked Infantile Spasms Syndrome (ISSX) is a catastrophic epilepsy of early childhood with intractable seizures, intellectual disability, and poor prognosis. A spectrum of mutations in the Aristaless-Related Homeobox gene (ARX) has been linked to ISSX, and downstream targets of this interneuron-expressed transcription factor are being defined. Recent advances combining in vitro and in vivo methods have unveiled complex interactions between Arx and its binding partners and their effects on cell migration and maturation that can help explain the diversity of ARX phenotypes. New mutant mouse models of Arx-induced pathology, including a recent human triplet-repeat expansion mutation with a phenotype of infantile spasms and electrographic seizures, provide valuable tools for exploring the pathophysiology of Arx and substrates for testing novel therapies.

Pathogenesis and new candidate treatments for infantile spasms and early life epileptic encephalopathies: A view from preclinical studies

“…An interesting disease modifying effect of neonatal estradiol, given prior to the first observation of spasms, was reported in the Arx (GCG)10+7 mice (Olivetti and Noebels 2012). Early (PN3-10) but not late (PN33-40) administration of estradiol restores the underlying interneuronopathy and ameliorates epilepsy in this model, indicating the existence of a sensitive period for the effects of estradiol.…”

Mechanisms of Epileptogenesis in Pediatric Epileptic Syndromes: Rasmussen Encephalitis, Infantile Spasms, and Febrile Infection-related Epilepsy Syndrome (FIRES)

“…ARX is a transcription factor that is involved in ventral telencephalon morphogenesis, migration of GABAergic neuronal progenitors, and early commitment of cholinergic neurons [75]. Seven transgenic mouse models with ARX loss-offunction or knockin mutations have been produced [76][77][78][79]. However, only two of these mouse strains exhibit epileptic spasms, suggesting a heterogeneity in the phenotype, similar to humans, which could be due to either the severity of genetic dysfunction stemming for the gene defect or other modifiers.…”

Building a zebrafish toolkit for investigating the pathobiology of epilepsy and identifying new treatments for epileptic seizures

“…Many of these genes encode neuronal proteins that regulate membrane excitability, such as ion channels, neurotransmitter receptors and transporters (Deng et al, 2014), or factors controlling synaptic vesicle formation, release and trafficking (Casillas-Espinosa et al, 2012). Mutations in genes that regulate the differentiation, migration and connectivity of GABA-ergic inhibitory interneurons (Peñagarikano et al, 2011;Olivetti and Noebels, 2012), or the activity of intercellular signalling cascades (Rivière et al, 2013), are also implicated in epilepsy. Moreover, novel approaches, including the systems-genetics approach of combining GWAS and transcriptomic analysis of human epileptic brain tissue, have begun to uncover networks of transcriptionally co-regulated gene networks that are characteristically associated with epileptogenesis (Johnson et al, 2015).…”