Pediatric refractory epilepsy is a broad phenotypic spectrum with great genetic heterogeneity. Next-generation sequencing (NGS) combined with Sanger sequencing could help to understand the genetic diversity and underlying disease mechanisms in pediatric epilepsy. Here, we report sequencing results from a cohort of 172 refractory epilepsy patients aged 0–14 years. The pathogenicity of identified variants was evaluated in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria. We identified 43 pathogenic or likely pathogenic variants in 40 patients (23.3%). Among these variants, 74.4% mutations (32/43) were de novo and 60.5% mutations (26/43) were novel. Patients with onset age of seizures ≤12 months had higher yields of deleterious variants compared to those with onset age of seizures > 12 months (P = 0.006). Variants in ion channel genes accounted for the greatest functional gene category (55.8%), with SCN1A coming first (16/43). 81.25% (13/16) of SCN1A mutations were de novo and 68.8% (11/16) were novel in Dravet syndrome. Pathogenic or likely pathogenic variants were found in the KCNQ2, STXBP1, SCN2A genes in Ohtahara syndrome. Novel deleterious variants were also found in West syndrome, Doose syndrome and glucose transporter type 1 deficiency syndrome patients. One de novo MECP2 mutation were found in a Rett syndrome patient. TSC1/TSC2 variants were found in 60% patients with tuberous sclerosis complex patients. Other novel mutations detected in unclassified epilepsy patients involve the SCN8A, CACNA1A, GABRB3, GABRA1, IQSEC2, TSC1, VRK2, ATP1A2, PCDH19, SLC9A6 and CHD2 genes. Our study provides novel insights into the genetic origins of pediatric epilepsy and represents a starting-point for further investigations into the molecular pathophysiology of pediatric epilepsy that could eventually lead to better treatments.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0392-5) contains supplementary material, which is available to authorized users.

Background Point and copy number variant mutations in the PRRT2 gene have been identified in a variety of paroxysmal disorders and different types of epilepsy. In this study, we analyzed the phenotypes and PRRT2‐related mutations in Chinese epilepsy children. Methods A total of 492 children with epilepsy were analyzed by whole exome sequencing (WES) and low‐coverage massively parallel CNV sequencing (CNV‐seq) to find the single nucleotide variants and copy number variations (CNVs). And quantitative polymerase chain reaction was utilized to verify the CNVs. Their clinical information was followed up. Results We found PRRT2‐related mutations in 19 patients (10 males and nine females, six sporadic cases and 13 family cases). Twelve point mutations, four whole gene deletion, and three 16p11.2 deletions were detected. The clinical features of 39 patients in 19 families included one early childhood myoclonic epilepsy (ECME), one febrile seizure (FS), two infantile convulsions with paroxysmal choreoathetosis (ICCA), six paroxysmal kinesigenic dyskinesias (PKD), 12 benign infantile epilepsy (BIE), and 17 benign familial infantile epilepsy (BFIE). All patients had normal brain MRI. Interictal EEG showed only one patient had generalized polyspike wave and five patients had focal transient discharges. Focal seizures originating in the frontal region were recorded in one patient, two from the temporal region, and two from the occipital region. Most patients were treated effectively with VPA or OXC, and the child with myoclonic seizures was not sensitive to antiepileptic drugs. Conclusion PRRT2 mutations can be inherited or de novo, mainly inherited. The clinical spectrum of PRRT2 mutation includes BIE, BFIE, ICCA, PKD, FS, and ECME. The PRRT2‐related mutations contained point mutation, whole gene deletion and 16p11.2 deletions, and large microdeletion mutations mostly de novo. It is the first report of PRRT2 mutation found in ECME. Our report expands the mutation and clinical spectrum of PRRT2‐related epilepsy.

Objective: To analyze the clinical feature, treatment, and prognosis of epileptic spasms (ES) in vitamin B6–dependent epilepsy, including patients with pyridoxine-dependent epilepsy (PDE) caused by ALDH7A1 mutation, pyridox(am)ine-5′-phosphate oxidase (PNPO) deficiency, and PLPBP deficiency.Methods: We analyzed data from a cohort of 54 cases with PDE, 13 cases with PNPO deficiency, and 2 cases with PLPBP deficiency and looked for the presentation of ES among them.Results: A total of 11 patients with the seizure presentation of ES have been collected. Among them, four patients carried mutations in ALDH7A1, six carried mutations in PNPO, and the remaining one carried mutation in PLPBP. The analysis of this cohort identified nine cases presenting as infantile spasms distributed in the three diseases and two cases presenting as Ohtahara syndrome diagnosed with PDE and PNPO deficiency, respectively. In the PDE and PLPBP deficiency groups, seizures were controlled by pyridoxine monotherapy, and the remaining one had refractory seizures due to secondary brain atrophy. In the groups with PNPO deficiency, one patient showed seizure-free when treated by PLP combined with valproic acid, three still had infrequent seizures treated by PLP monotherapy or pyridoxine or PLP combined with other antiseizure medications, and two died. In two cases presenting as Ohtahara syndrome, after regular treatment, one showed seizure-free, the others showed a marked decrease in seizure frequency, and they both showed an improvement in EEG.Significance: ES might be a common form of seizures in PNPO deficiency, and EEG presented as hypsarrhythmia or a burst suppression pattern. It is difficult for pyridoxine to control frequent seizures caused by secondary brain injury. In our PNPO deficiency cohort, patients with infantile spasms did not respond better to PLP than pyridoxine. Timely and correct treatment could prevent the transformation of the child’s disease from Ohtahara syndrome and infantile spasms to subsequent epileptic encephalopathy or refractory epilepsy.

ObjectiveTo determine the contribution of genetic etiologies in epilepsy with photosensitivity.MethodsA total of 35 epileptic patients with genetic photosensitivity from January 2019 to May 2021 were analyzed.ResultsPathogenic variants were identified in 35 patients, including SCN1A(7) CHD2(6), TPP1(3), SYNGAP1(3), GABRA1(2), GABRG2(1), KCTD7(1), MFSD8(1), KCNC1(1) GBA(1), CACNA1A(1), KCNMA1(1), FLNA(1), SZT2(1), SLC2A1(1), 5q33.2-34del(1), and mitochondrial variants(3). The predominant epileptic syndrome was progressive myoclonus epilepsy (PME) and Dravet syndrome, while the most common seizure type in both spontaneous seizures and photoconvulsive response (PCR) was myoclonic seizures. The abnormal EEG background and brain MRI were mainly seen in the PME patients. In PME, initial low-frequencies (1–6 Hz) photosensitivity was observed in 70% (7/10) of patients. Among the other patients, 12 patients (48.0%, 12/25) had photosensitivity at initial low -frequencies and 12 patients (48.0%, 12/25) had photosensitivity at initial middle frequencies (6–20 Hz). At the 1-year follow-up, 77.7% (21/27) still remained photosensitive.ConclusionThe most common genes for epilepsy with genetic photosensitivity are SCN1A and CHD2, and the most common syndromes are PME and Dravet syndrome. MFSD8, KCNMA1, SZT2, FLNA, and SLC2A1 variants might be candidate genes for photosensitivity. PPRs at initial low-frequencies may be a marker of PME, and the most typical feature of genetic photosensitivity may be low- or middle- frequencies induced PPRs. Photosensitivity in epilepsy with genetic photosensitivity may be difficult to disappear in a short period of time.