Persistent sodium currents in SCN1A developmental and degenerative epileptic dyskinetic encephalopathy

Abstract

Pathogenic variants in the voltage-gated sodium channel gene (SCN1A) are amongst the most common genetic causes of childhood epilepsies. There is considerable heterogeneity in both the types of causative variants and associated phenotypes; a recent expansion of the phenotypic spectrum of SCN1A associated epilepsies now includes an early onset severe developmental and epileptic encephalopathy with regression and a hyperkinetic movement disorder. Herein, we report a female with a developmental and degenerative epileptic-dyskinetic encephalopathy, distinct and more severe than classic Dravet syndrome. Clinical diagnostics indicated a paternally inherited c.5053G>T; p. A1685S variant of uncertain significance in SCN1A. Whole-exome sequencing detected a second de novo mosaic (18%) c.2345G>A; p. T782I likely pathogenic variant in SCN1A (maternal allele). Biophysical characterisation of both mutant channels in a heterologous expression system identified gain-of-function effects in both, with a milder shift in fast inactivation of the p. A1685S channels; and a more severe persistent sodium current in the p. T782I. Using computational models, we show that large persistent sodium currents induce hyperexcitability in individual cortical neurons, thus relating the severe phenotype to the empirically quantified sodium channel dysfunction. These findings further broaden the phenotypic spectrum of SCN1A associated epilepsies and highlight the importance of testing for mosaicism in epileptic encephalopathies. Detailed biophysical evaluation and computational modelling further highlight the role of gain-of-function variants in the pathophysiology of the most severe phenotypes associated with SCN1A.

The L1624Q Variant in SCN1A Causes Familial Epilepsy Through a Mixed Gain and Loss of Channel Function

“…The L1624Q variant falls into a growing class of mixed loss- and gain-of-function variants in Na V 1.1 ( Ohmori et al, 2002 ; Claes et al, 2003 ; Rhodes et al, 2004 ; Rhodes et al, 2005 ; Volkers et al, 2011 ; Peters et al, 2016 ; Sadleir et al, 2017 ; Berecki et al, 2019 ; Brunklaus and Lal, 2020 ; Gorman et al, 2021 ). These variants are characterized by multiple defects that cause opposing effects on channel activation and inactivation.…”

“…The mixed variant T226M has been associated with a more severe early onset, atrophy of the brain, and dyskinesia due to a lack of depolarization block ( Sadleir et al, 2017 ; Berecki et al, 2019 ). We recently reported a case of a large inward persistent current causing drug resistant and fatal epilepsy with atrophy and a dyskinetic disorder ( Gorman et al, 2021 ). Drug resistance is not uncommon in epilepsy associated with SCN1A variants, and has also been reported in many of the mixed-function variants discussed above ( Claes et al, 2003 ; Fujiwara et al, 2003 ; Rhodes et al, 2004 ; Sadleir et al, 2017 ).…”

“…To simulate how L1624Q-dependent perturbations on channel gating alter cortical neuron firing, we modified prior models of pyramidal neuron firing ( Traub et al, 1991 ; Destexhe et al, 1994 ). The methodology is described in prior publications ( Peters et al, 2016 ; Gorman et al, 2021 ) and codes to run cortical neuron simulations in Python are freely available online ( https://github.com/roschkoenig/SodMod ). The increased rate of inactivation onset in the L1624Q variant at 37°C was implemented by multiplying the rate of inactivation onset by 1.485, reflecting the average increase in inactivation rates measured between −30 and +20 mV at 37°C.…”

“…However, SCN1A gene variants are also a recognized cause for epilepsies and neurodevelopmental disorders outside the Dravet syndrome spectrum—ranging from milder phenotypes such as generalized epilepsy with febrile seizures plus ( Escayg et al, 2000 ), to other epilepsy syndromes such as myoclonic astatic epilepsy, epilepsy of infancy with migrating focal seizures, or even to recently described more severe early onset epileptic encephalopathies with neurodegeneration and dyskinesia ( Sadleir et al, 2017 ; Beck et al, 2019 ; Gorman et al, 2021 ). With increased genetic testing, SCN1A variants have been described in patients with focal epilepsies ( Vezyroglou et al, 2020 )—both in patients that were candidates for epilepsy surgery, and those with self-limiting focal epilepsies of childhood.…”

Damaging novel mutations in PIGN cause developmental epileptic-dyskinetic encephalopathy: a case report

“…Our patient only manifested DEE and PNKD, and no visceral abnormalities or dysmorphic features were observed until the age of 6 years. A novel term, namely developmental and epileptic-dyskinetic encephalopathy (DEDE), has been used to describe a subset of children with DEE and a hyperkinetic movement disorder including choreoathetosis, dyskinesia, dystonia, and non-epileptic myoclonus [ 10 , 11 ]. DEDE is characterized by multiple types of refractory epilepsy, profound intellectual disability, and hyperkinetic movement disorder which often appears after epilepsy [ 10 , 11 ].…”