Early epileptic encephalopathy associated with SCN2A mutations: clinical and genetic description of eight novel patients

Background. A large number of single gene disorders with seizures in clinical picture has been described. Among them, a special place is held by early-onset epileptic encephalopathies (EEE) – a genetically diverse group of disorders characterized by manifestation of seizures in the first 2 years of life and severe progressing course. Currently, 58 genetic variants of EEE has been identified.

The objective is to analyze the incidence, clinical and genetic characteristic of type II EEE in a sample of patients from Russia identified by whole exome sequencing using next generation sequencing.

Materials and methods. The patient sample included 67 children (35 boys and 32 girls) with ages varying from 4 months to 10 years. All patients underwent neurological examination using the standard techniques. Monitoring of electroencephalography (EEG) was performed in accordance with the International 10–20 system. For magnetic resonance imaging, tomographs with magnetic induction of 1.5 and 3.0 T were used. The identified changes were confirmed by Sanger sequencing using DNA from the patients and their parents.

Results. In total, 67 patients with EEE were diagnosed, 8 of which had causational mutations in the SCN2A gene: p.Leu1611Pro (c.4832T>C), p.Cys728* (c.2184C>A), p.Arg607* (c.1819C>T), p.Val1325Ile (c.623T>C), p.Leu419Met (c.1255T>A), p.Asp1487Glu (c.4461C>A), p.Val208Ala (c.3973G>A), p.Gln1211Lys (c.3631G>A). Analysis of parent DNA had shown that all mutations appeared de novo. At the time of disease onset, all patients had multiregional epileptiform activity per EEG. Focal seizures, myoclonic seizures, and epileptic spasms were the most common types of seizures in the patients. The majority of patients (5/8) had diffuse muscular hypotonia. All patients had pronounced mental deficiency. All patients received more than 2 therapy regimens (including hormonal therapy and ketogenic diet) but full remission wasn’t obtained. In some patients, partial positive dynamic was registered with hormonal therapy and sodium channel blockers. Various mutations in the SCN2A gene caused a similar clinical picture but had different functional significance which determined the effectiveness of anti-epileptic therapy.

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