-related epilepsy of infancy with migrating focal seizures: report of a variant with apparent gain- and loss-of-function effects.

Publication Type:

Journal Article


J Neurophysiol, Volume 127, Issue 5, p.1388-1397 (2022)


Epilepsy, Female, Humans, Infant, Mutation, NAV1.2 Voltage-Gated Sodium Channel, Phenotype, Seizures


<p>SCN2A encodes a voltage-gated sodium channel (Na1.2) expressed throughout the central nervous system in predominantly excitatory neurons. Pathogenic variants in are associated with epilepsy and neurodevelopmental disorders. Genotype-phenotype correlations have been described, with loss-of-function variants typically being associated with neurodevelopmental delay and later-onset seizures, whereas gain-of-function variants more often result in early infantile-onset epilepsy. However, the true electrophysiological effects of most disease-causing variants have yet to be characterized. We report an infant who presented with migrating focal seizures in the neonatal period. She was found to have a mosaic c.2635G>A, p.Gly879Arg variant in . Voltage-clamp studies of the variant expressed on adult and neonatal Na1.2 isoforms demonstrated a mixed gain and loss of function, with predominantly a loss-of-function effect with reduced cell surface expression and current density. Additional small electrophysiological alterations included a decrease in the voltage dependence of activation and an increase in the voltage dependence of inactivation. This finding of a predominantly loss-of-function effect was unexpected, as the infant's early epilepsy onset would have suggested a predominantly gain-of-function effect. This case illustrates that our understanding of genotype-phenotype correlations is still limited and highlights the complexity of the underlying electrophysiological effects of variants. Voltage-gated sodium channels play an important role in the central nervous system, mutations in which have been reported to be responsible for epilepsy. We report here an infant presenting with epilepsy of infancy with migrating focal seizures (EIMFS) in the neonatal period with a mosaic c.2635G>A, resulting in a p.Gly879Arg missense mutation on the gene encoding Na1.2 sodium channels. Biophysical characterization of this variant revealed a mixture of gain- and loss-of-function effects.</p>

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