Abstract
Dravet syndrome is the prototype of SCN1A-mutation associated epilepsies. It is characterised by prolonged seizures, typically provoked by fever. We describe the evaluation of an SCN1A mutation in a child with early-onset temperature-sensitive seizures. The patient carries a heterozygous missense variant (c3818C > T; pAla1273Val) in the NaV1.1 brain sodium channel. We compared the functional effects of the variant vs. wild type NaV1.1 using patch clamp recordings from channels expressed in Chinese Hamster Ovary Cells at different temperatures (32, 37, and 40 °C). The variant channels produced a temperature-dependent destabilization of activation and fast inactivation. Implementing these empirical abnormalities in a computational model predicts a higher threshold for depolarization block in the variant, particularly at 40 °C, suggesting a failure to autoregulate at high-input states. These results reveal direct effects of abnormalities in NaV1.1 biophysical properties on neuronal dynamics. They illustrate the value of combining cellular measurements with computational models to integrate different observational scales (gene/channel to patient).
Highlights
To channels with altered rates and voltage dependence of gating can impair electrical signalling and, in the case of neuronal channels, lead to different epilepsy syndromes
We present a patient with an early-onset, temperature-sensitive epilepsy phenotype and a heretofore uncharacterised de novo heterozygous SCN1A mutation (c.3818C >T, ClinVar Accession: RCV000180969.1) coding for a mutant in DIIIS2 of the NaV1.1 channel (p.Ala1273Val)
Integrating these empirical results in computational models of action potential dynamics at the membrane of a cortical neuron, we specify the functional effects of the mutation and describe a mechanism that leads to temperature-sensitive epilepsy
Summary
To channels with altered rates and voltage dependence of gating can impair electrical signalling and, in the case of neuronal channels, lead to different epilepsy syndromes. Using patch-clamp characterisation of channel properties, we identify dynamic, temperature-dependent differences from wild type (WT) Integrating these empirical results in computational models of action potential dynamics at the membrane of a cortical neuron, we specify the functional effects of the mutation and describe a mechanism that leads to temperature-sensitive epilepsy. This child was first admitted at the age of 6 months with a brief, self-terminating febrile seizure with a right-sided predominance of his twitching movements. A proportion of these seizures were apparently provoked by a hot bath, or whilst playing in a very warm environment
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