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The SCN8A encephalopathy mutation p.Ile1327Val displays elevated sensitivity to the anticonvulsant phenytoin
Author(s) -
Barker Bryan S.,
Ottolini Matteo,
Wag Jacy L.,
Hollander Rachel M.,
Meisler Miriam H.,
Patel Manoj K.
Publication year - 2016
Publication title -
epilepsia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.687
H-Index - 191
eISSN - 1528-1167
pISSN - 0013-9580
DOI - 10.1111/epi.13461
Subject(s) - phenytoin , sodium channel , epilepsy , anticonvulsant , sodium channel blocker , encephalopathy , chemistry , medicine , neuroscience , anesthesia , pharmacology , psychology , sodium , organic chemistry
Summary Objective SCN8A encephalopathy (early infantile epileptic encephalopathy; EIEE13) is caused by gain‐of‐function mutations resulting in hyperactivity of the voltage‐gated sodium channel Na v 1.6. The channel is concentrated at the axon initial segment (AIS) and is involved in establishing neuronal excitability. Clinical features of SCN8A encephalopathy include seizure onset between 0 and 18 months of age, intellectual disability, and developmental delay. Seizures are often refractory to treatment with standard antiepileptic drugs, and sudden unexpected death in epilepsy (SUDEP) has been reported in approximately 10% of patients. In a recent study, high doses of phenytoin were effective in four patients with SCN8A encephalopathy. In view of this observation, we have investigated the relationship between the functional effect of the SCN8A mutation p.Ile1327Val and its response to phenytoin. Methods The mutation was introduced into the Scn8a cDNA by site‐directed mutagenesis. Channel activity was characterized in transfected ND7/23 cells. The effects of phenytoin (100 μ m ) on mutant and wild‐type (WT) channels were compared. Results Channel activation parameters were shifted in a hyperpolarizing direction in the mutant channel, whereas inactivation parameters were shifted in a depolarizing direction, increasing Na channel window current. Macroscopic current decay was slowed in I1327V channels, indicating an impairment in the transition from open state to inactivated state. Channel deactivation was also delayed, allowing more channels to remain in the open state. Phenytoin (100 μ m ) resulted in hyperpolarized activation and inactivation curves as well as greater tonic block and use‐dependent block of I1327V mutant channels relative to WT. Significance SCN8A – I1327V is a gain‐of‐function mutation with altered features that are predicted to increase neuronal excitability and seizure susceptibility. Phenytoin is an effective inhibitor of the mutant channel and may be of use in treating patients with gain‐of‐function mutations of SCN8A .