Sequencing-based studies have identified novel risk genes associated with severe epilepsies and revealed an excess of rare deleterious variation in less-severe forms of epilepsy. To identify the shared and distinct ultra-rare genetic risk factors for different types of epilepsies, we performed a whole-exome sequencing (WES) analysis of 9,170 epilepsy-affected individuals and 8,436 controls of European ancestry. We focused on three phenotypic groups: severe developmental and epileptic encephalopathies (DEEs), genetic generalized epilepsy (GGE), and non-acquired focal epilepsy (NAFE). We observed that compared to controls, individuals with any type of epilepsy carried an excess of ultra-rare, deleterious variants in constrained genes and in genes previously associated with epilepsy; we saw the strongest enrichment in individuals with DEEs and the least strong in individuals with NAFE. Moreover, we found that inhibitory GABA A receptor genes were enriched for missense variants across all three classes of epilepsy, whereas no enrichment was seen in excitatory receptor genes. The larger gene groups for the GABAergic pathway or cation channels also showed a significant mutational burden in DEEs and GGE. Although no single gene surpassed exome-wide significance among individuals with GGE or NAFE, highly constrained genes and genes encoding ion channels were among the lead associations; such genes included CACNA1G, EEF1A2, and GABRG2 for GGE and LGI1, TRIM3, and GABRG2 for NAFE. Our study, the largest epilepsy WES study to date, confirms a convergence in the genetics of severe and less-severe epilepsies associated with ultra-rare coding variation, and it highlights a ubiquitous role for GABAergic inhibition in epilepsy etiology.

Mutations in PRRT2 have been described in paroxysmal kinesigenic dyskinesia (PKD) and infantile convulsions with choreoathetosis (PKD with infantile seizures), and recently also in some families with benign familial infantile seizures (BFIS) alone. We analyzed PRRT2 in 49 families and three sporadic cases with BFIS only of Italian, German, Turkish, and Japanese origin and identified the previously described mutation c.649dupC in an unstable series of nine cytosines to occur in 39 of our families and one sporadic case (77% of index cases). Furthermore, three novel mutations were found in three other families, whereas 17% of our index cases did not show PRRT2 mutations, including a large family with late-onset BFIS and febrile seizures. Our study further establishes PRRT2 as the major gene for BFIS alone.

The frequent co-occurrence of migraine and TTH symptoms suggests the presence of a common pathogenesis.

This study evaluated whether a correlation exists between increased serum bilirubin and neuron-specific enolase (NSE) assays (a biochemical index of neuronal damage) and auditory neuropathy. Nineteen term neonates without hemolysis whose serum bilirubin levels were above 20 mg/dl and 27 healthy term newborns with bilirubin levels <13 mg/dl were included in the study. Auditory brainstem responses (ABRs) and transient evoked otoacoustic emissions (TEOAEs) of patients with hyperbilirubinemia were obtained before discharge. This preliminary study did not show any correlation between the serum NSE and bilirubin values. However, infants who had auditory neuropathy had significantly higher NSE levels, and thus these patients, being in the high-risk group, need close follow-up.

Cytogenic testing is routinely applied in most neurological centres for severe paediatric epilepsies. However, which characteristics of copy number variants (CNVs) confer most epilepsy risk and which epilepsy subtypes carry the most CNV burden, have not been explored on a genome-wide scale. Here, we present the largest CNV investigation in epilepsy to date with 10 712 European epilepsy cases and 6746 ancestry-matched controls. Patients with genetic generalized epilepsy, lesional focal epilepsy, non-acquired focal epilepsy, and developmental and epileptic encephalopathy were included. All samples were processed with the same technology and analysis pipeline. All investigated epilepsy types, including lesional focal epilepsy patients, showed an increase in CNV burden in at least one tested category compared to controls. However, we observed striking differences in CNV burden across epilepsy types and investigated CNV categories. Genetic generalized epilepsy patients have the highest CNV burden in all categories tested, followed by developmental and epileptic encephalopathy patients. Both epilepsy types also show association for deletions covering genes intolerant for truncating variants. Genome-wide CNV breakpoint association showed not only significant loci for genetic generalized and developmental and epileptic encephalopathy patients but also for lesional focal epilepsy patients. With a 34-fold risk for developing genetic generalized epilepsy, we show for the first time that the established epilepsy-associated 15q13.3 deletion represents the strongest risk CNV for genetic generalized epilepsy across the whole genome. Using the human interactome, we examined the largest connected component of the genes overlapped by CNVs in the four epilepsy types. We observed that genetic generalized epilepsy and non-acquired focal epilepsy formed disease modules. In summary, we show that in all common epilepsy types, 1.5–3% of patients carry epilepsy-associated CNVs. The characteristics of risk CNVs vary tremendously across and within epilepsy types. Thus, we advocate genome-wide genomic testing to identify all disease-associated types of CNVs.

No abstract

This study aimed to investigate the relationship among lipid peroxidation, subsequent activation of scavenger enzymes (superoxide dismutase and glutathione peroxidase), and the presence of structural abnormality in 52 epileptic children receiving monotherapy (medically responsive) or polytherapy (medically intractable). Plasma lipid peroxidation in epileptic patients with abnormal magnetic resonance imaging (MRI) findings significantly increased as compared with that of 16 healthy children (P < .05), whereas antioxidant enzymes were not significantly affected. Both medically controlled and intractable children with normal MRI had higher activities of superoxide dismutase than those of controls (P < .05). The activity of superoxide dismutase in epileptic patients with structural abnormality did not significantly change as compared with controls. Activity of glutathione peroxidase in all of the epileptic children was not significantly different from controls. The activity of antioxidant enzymes or plasma malonyldialdehyde levels did not correlate with duration of epilepsy, frequency of seizures (> one seizure per month or not), and the presence or localization (focal, multifocal, or generalized) of electroencephalographic or MRI abnormalities. Increased plasma lipid peroxidation may be causally related to the presence of structural abnormality rather than ongoing epileptic activity or therapy status.

The authors compared interictal and ictal abnormalities from chronic intracranial recordings in children with Taylor-type cortical dysplasia (TTCD) and nondysplastic lesions. Interictal epileptiform discharges and ictal patterns were retrospectively analyzed in 13 children with TTCD and 12 children with nondysplastic lesions (tumor, 4; gliosis, 8). Features analyzed and compared between groups included the morphologic and temporal characteristics and field distribution of ictal and interictal patterns and rapidity of ictal propagation. The frequency of runs of interictal continuous epileptiform discharges (CEDs) or bursts of fast activity did not differ significantly between dysplastic and nondysplastic tissue. Fast frequencies characterized the majority of seizure onsets (49/67) in dysplastic patients and repetitive spikes were more frequent at seizure onset (31/56) in nondysplastic patients (P < 0.002). Field of ictal onset was limited to adjacent cortex and independent of histology. The interval between seizure onset and spread to adjacent or nonadjacent cortex was significantly shorter in dysplastic than nondysplastic patients. Interictal EEG patterns are not specific markers of dysplastic cortex but the morphology of ictal onset differs significantly with dysplastic cortex showing significantly more rapid propagation than nondysplastic cortex. These findings suggest that markers other than CEDs physiologically characterize dysplastic cortex and that children with TTCD exhibit more widespread excitability of neural pathways.