Loss-of-function variants in the KCNQ5 gene are implicated in genetic generalized epilepsies.

BACKGROUND: De novo missense variants in KCNQ5, encoding the voltage-gated K+ channel KV7.5, have been described to cause developmental and epileptic encephalopathy (DEE) or intellectual disability (ID). We set out to identify disease-related KCNQ5 variants in genetic generalized epilepsy (GGE) and their underlying mechanisms. METHODS: 1292 families with GGE were studied by next-generation sequencing. Whole-cell patch-clamp recordings, biotinylation and phospholipid overlay assays were performed in mammalian cells combined with homology modelling. FINDINGS: We identified three deleterious heterozygous missense variants, one truncation and one splice site alteration in five independent families with GGE with predominant absence seizures; two variants were also associated with mild to moderate ID. All missense variants displayed a strongly decreased current density indicating a loss-of-function (LOF). When mutant channels were co-expressed with wild-type (WT) KV7.5 or KV7.5 and KV7.3 channels, three variants also revealed a significant dominant-negative effect on WT channels. Other gating parameters were unchanged. Biotinylation assays indicated a normal surface expression of the variants. The R359C variant altered PI(4,5)P2-interaction. INTERPRETATION: Our study identified deleterious KCNQ5 variants in GGE, partially combined with mild to moderate ID. The disease mechanism is a LOF partially with dominant-negative effects through functional deficits. LOF of KV7.5 channels will reduce the M-current, likely resulting in increased excitability of KV7.5-expressing neurons. Further studies on network level are necessary to understand which circuits are affected and how this induces generalized seizures. FUNDING: DFG/FNR Research Unit FOR-2715 (Germany/Luxemburg), BMBF rare disease network Treat-ION (Germany), foundation 'no epilep' (Germany).

Predictive factors and prognostic value for status epilepticus in newborns.

OBJECTIVES: To evaluate the predictive factors for status epilepticus (SE) in neonates and prognostic factors for patient outcomes in newborns suffering either isolated seizures or SE. METHODS: A retrospective single-center study from January 2010 to December 2014, included 91 newborns who had neonatal seizures. Among them, 50 newborns experienced SE and 41 newborns presented isolated seizures only. SE was defined as a single seizure lasting more than 15 min or repeated seizures without return to preictal neurological baseline for more than 15 min. Isolated seizures were defined as one single seizure lasting less than 15 min or more seizures with complete recovery of consciousness between seizures. Perinatal and electroclinical data were recorded. Outcomes were evaluated at one year follow up. RESULTS: In multivariate analysis, the factors identified as being predictive of SE were a severely abnormal initial neurological examination (OR 15.7, 95% CI (3.8-109) p = 0.00075) and hypoglycaemia (OR 6.8, 95% CI (1.5-49.2) p = 0.024), found mostly in newborns with hypoxic-ischemic encephalopathy. When studying our global cohort, SE was found to be a negative prognostic factor for outcome only in univariate analysis. In newborns with isolated seizures only, the postictal clinical examination results were the only independent prognostic factor found, normal results being associated with a more favorable evolution (OR 48.9, 95% CI (7.16-571) p = 0.0003). CONCLUSION: Two independent risk factors for SE in newborns have been identified: a severely abnormal initial neurological examination and hypoglycaemia. In newborns with isolated seizures, the only positive prognostic factor was found to be a normal postictal clinical examination.

Functional connectivity of insular efferences.

OBJECTIVES: The aim of our study was to explore the functional connectivity between the insula and other cortical regions, in human, using cortico-cortical evoked potentials (CCEPs) EXPERIMENTAL DESIGN: We performed intra-cerebral electrical stimulation in eleven patients with refractory epilepsy investigated with depth electrodes, including 39 targeting the insula. Electrical stimulation consisted of two series of 20 pulses of 1-ms duration, 0.2-Hz frequency, and 1-mA intensity delivered at each of the 39 insular bipoles. Rates of connectivity were reported whenever a noninsular cortical region was tested by at least ten stimulating/recording electrode pairs in three or more patients RESULTS: Significant CCEPs were elicited in 193 of the 578 (33%) tested connections, with an average latency of 33 ± 5 ms. The highest connectivity rates were observed with the nearby perisylvian structures (59%), followed by the pericentral cortex (38%), the temporal neocortex (28%), the lateral parietal cortex (26%), the orbitofrontal cortex (25%), the mesial temporal structures (24%), the dorsolateral frontal cortex (15%), the temporal pole (14%), and the mesial parietal cortex (11%). No connectivity was detected in the mesial frontal cortex or cingulate gyrus. The pattern of connectivity also differed between the five insular gyri, with greater connectivity rate for the posterior short gyrus (49%), than for the middle short (29%), and two long gyri (28 and 33%) CONCLUSION: The human insula is characterized by a rich and complex connectivity that varies as a function of the insular gyrus and appears to partly differ from the efferences described in nonhuman primates.

Similar semiology of epileptic and psychogenic nonepileptic seizures recorded during stereo-EEG.

We report two adolescents with refractory seizure disorders in whom both epileptic and psychogenic nonepileptic seizures (PNES) were recorded with intracerebral EEG. The ictal phenomenology of epileptic seizures (ES) and PNES, consisting of hypermotor attacks in the first patient and left-sided painful episodes in the second patient, proved remarkably similar in both cases, highlighting the difficulties which can arise with the distinction of epileptic seizures and PNES based on ictal phenomenology alone.

Epileptic encephalopathies of the Landau-Kleffner and continuous spike and waves during slow-wave sleep types: genomic dissection makes the link with autism.

PURPOSE: The continuous spike and waves during slow-wave sleep syndrome (CSWSS) and the Landau-Kleffner (LKS) syndrome are two rare epileptic encephalopathies sharing common clinical features including seizures and regression. Both CSWSS and LKS can be associated with the electroencephalography pattern of electrical status epilepticus during slow-wave sleep and are part of a clinical continuum that at its benign end also includes rolandic epilepsy (RE) with centrotemporal spikes. The CSWSS and LKS patients can also have behavioral manifestations that overlap the spectrum of autism disorders (ASD). An impairment of brain development and/or maturation with complex interplay between genetic predisposition and nongenetic factors has been suspected. A role for autoimmunity has been proposed but the pathophysiology of CSWSS and of LKS remains uncharacterized. METHODS: In recent years, the participation of rare genomic alterations in the susceptibility to epileptic and autistic disorders has been demonstrated. The involvement of copy number variations (CNVs) in 61 CSWSS and LKS patients was questioned using comparative genomic hybridization assays coupled with validation by quantitative polymerase chain reaction (PCR). KEY FINDINGS: Whereas the patients showed highly heterogeneous in genomic architecture, several potentially pathogenic alterations were detected. A large number of these corresponded to genomic regions or genes (ATP13A4, CDH9, CDH13, CNTNAP2, CTNNA3, DIAPH3, GRIN2A, MDGA2, SHANK3) that have been either associated with ASD for most of them, or involved in speech or language impairment, or in RE. Particularly, CNVs encoding cell adhesion proteins (cadherins, protocadherins, contactins, catenins) were detected with high frequency (≈20% of the patients) and significant enrichment (cell adhesion: p = 0.027; cell adhesion molecule binding: p = 9.27 × 10(-7)). SIGNIFICANCE: Overall our data bring the first insights into the possible molecular pathophysiology of CSWSS and LKS. The overrepresentation of cell adhesion genes and the strong overlap with the genetic, genomic and molecular ASD networks, provide an exciting and unifying view on the clinical links among CSWSS, LKS, and ASD.