Clinical phenotype, gene mutation and application of targeted next generation sequencing in patients with early-onset epileptic encephalopathy

Abstract

Objective To study the clinical features and gene mutations of early-onset epileptic encephalopathy (EOEE) and to explore the application in pathogenic diagnosis of EOEE by next generation sequencing.  Methods The clinical data of 68 cases diagnosed with unexplained EOEE between June 2014 and December 2017 were obtained and analyzed. Specimens were collected from the selected children and their parents. Next generation sequencing was used to detect epilepsy ? related genes, and Sanger sequencing was performed to verify the results and confirm the source of parents, further to identify suspected pathogenic mutations of EOEE. Results Among 68 cases with EOEE, 18 cases (26.47%) were detected with epilepsy?related genes. One was diagnosed as pyridoxine dependent epilepsy (PDE), which was caused by ALDH7A1 mutation. One was diagnosed as thiamine metabolism dysfunction syndrome 2 (THMD2), which was caused by SLC19A3 mutation. Among 13 cases of epilepsy syndrome, 6 cases were diagnosed as Dravet's syndrome (DS), 5 caused by SCN1A missense mutation and one by SCN1A nonsense mutation; 4 cases were diagnosed as infantile spasm (IS), one caused by TSC1 nonsense mutation but the pathogenicity can not be identified while pathogenic mutations were not detected in other 3 cases; 2 cases were diagnosed as Ohtahara's syndrome (OS), one caused by STXBP1 missense mutation and pathogenic mutation was not found in the other; one case of malignant migrating partial seizures in infancy (MMPEI) was not found the pathogenic mutations. Among 53 cases with non-specific EOEE, suspected pathogenic mutations were detected in 9 cases: one case of  CN8A missense mutation, one case of KCNQ2 missense mutation, one case of KCNH5 missense mutation, one case of CACNA1A missense mutation, 2 cases of CDKL5 nonsense mutation, one case of CDKL5 frame-shift mutation, one case of PCDH19 nonsense mutation and one case of GRIN2A missense mutation. All cases were treated by 2 and more antiepileptic drugs (AEDs), one case of PDE was given vitamin B6 20 mg/(kg·d), and one case of THMD2 was given vitamin B1 25 mg/(kg·d) and biotin 2 mg/(kg·d). After followed by 6 months to 8 years, 15 cases (22.06%) were seizure free, 21 cases (30.88% ) were part of control and 32 cases (47.06% ) were out of control.  Conclusions The clinical phenotypes of children with unexplained EOEE are varied. One case was diagnosed as PDE and one as THMD2 after gene sequencing. After treated by etiological treatment, patients with remediable genetic disease were seizure free. Some gene sites were denovo mutations which have not been reported such as missense mutation for SCN1A, STXBP1, KCNH5, CACNA1A, frame-shift mutation for CDKL5, and onsense mutation for PCDH19, which enriched the mutation spectrum of EOEE.

DOI: 10.3969/j.issn.1672-6731.2018.06.008