Developmental epileptic encephalopathy caused by a de novo mutation in the SCN8A gene

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Developmental epileptic encephalopathy is characterized by a malignant course of refractory epilepsy and a growing defect in mental and motor development. To date, determinant genes have been identified for most of these conditions. This condition is also caused by mutations in the SCN8A gene of a voltage-gated sodium channel, which is detected in about 1% of children with early infantile epileptic encephalopathies. SCN8A gene mutations result in both an increase (gain-of-function, GOF mutation) and a decrease (loss-of-function, LOF mutation) in NaV1.6 sodium channel function, leading to a decrease in current amplitude and a depolarizing shift. With GOF mutation, hypotension, cerebral visual dysfunction, dyskinesia, ataxia, and epileptic seizures are mainly present as bilateral tonic and focal seizures and, in most cases, lead to epileptic encephalopathy. With the LOF mutation, seizures (absences, bilateral tonic-clonic myoclonic seizures) may not appear, while cognitive impairment, movement disorders, and autistic traits are present. Anticonvulsant regimens include non-selective sodium channel blockers, GABA agonists, Na+ and Ca2+ channel blockers, and other agents. A specific feature of the phenotype is a relatively high probability of exacerbation of the epilepsy during anticonvulsant selection, which requires special care and caution from the doctor. As an illustration of the most typical features of the condition, a clinical case of severe refractory epilepsy with a developmental disorder in an infant is presented. The disease progressed despite all attempts to select therapy. Treatment with corticosteroids gave a temporary effect, and when the drug was discontinued, the frequency and severity of seizures increased, suggesting the GOF scenario; however, genetic confirmation was inaccessible. The authors believe that the prospects for treating such conditions are determined primarily by progress in the development of new drugs, including oligonucleotides and selective inhibitors of NaV1.6 channels.

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