KCNQ2 R144 variants cause neurodevelopmental disability with language impairment and autistic features without neonatal seizures through a gain-of-function mechanism

Prior studies have revealed remarkable phenotypic heterogeneity in KCNQ2-related disorders, correlated with effects on biophysical features of heterologously expressed channels. Here, we assessed phenotypes and functional properties associated with KCNQ2 missense variants R144W, R144Q, and R144G. We also explored in vitro blockade of channels carrying R144Q mutant subunits by amitriptyline

Mutations in GABRB3

Objective: To examine the role of mutations in GABRB3 encoding the b3 subunit of the GABAA receptor in individual patients with epilepsy with regard to causality, the spectrum of genetic variants, their pathophysiology, and associated phenotypes. Methods: We performed massive parallel sequencing of GABRB3 in 416 patients with a range of epileptic encephalopathies and childhood-onset epilepsies and recruited additional patients with epilepsy with GABRB3 mutations from other research and diagnostic programs. Results: We identified 22 patients with heterozygous mutations in GABRB3, including 3 probands frommultiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy withmyoclonic-atonic seizures to West syndrome and other types of severe, early-onset epileptic encephalopathies. Electrophysiologic analysis of 7 mutations in Xenopus laevis oocytes, using coexpression of wild-type or mutant beta(3), together with alpha(5) and gamma(2s) subunits and an automated 2-microelectrode voltage-clamp system, revealed reduced GABA-induced current amplitudes or GABA sensitivity for 5 of 7 mutations. Conclusions: Our results indicate that GABRB3 mutations are associated with a broad phenotypic spectrum of epilepsies and that reduced receptor function causing GABAergic disinhibition represents the relevant disease mechanism

<i>GRIN2A</i>-related disorders:genotype and functional consequence predict phenotype

Alterations of the N-methyl-d-aspartate receptor (NMDAR) subunit GluN2A, encoded by GRIN2A, have been associated with a spectrum of neurodevelopmental disorders with prominent speech-related features, and epilepsy. We performed a comprehensive assessment of phenotypes with a standardized questionnaire in 92 previously unreported individuals with GRIN2A-related disorders. Applying the criteria of the American College of Medical Genetics and Genomics to all published variants yielded 156 additional cases with pathogenic or likely pathogenic variants in GRIN2A, resulting in a total of 248 individuals. The phenotypic spectrum ranged from normal or near-normal development with mild epilepsy and speech delay/apraxia to severe developmental and epileptic encephalopathy, often within the epilepsy-aphasia spectrum. We found that pathogenic missense variants in transmembrane and linker domains (misTMD+Linker) were associated with severe developmental phenotypes, whereas missense variants within amino terminal or ligand-binding domains (misATD+LBD) and null variants led to less severe developmental phenotypes, which we confirmed in a discovery (P = 10-6) as well as validation cohort (P = 0.0003). Other phenotypes such as MRI abnormalities and epilepsy types were also significantly different between the two groups. Notably, this was paralleled by electrophysiology data, where misTMD+Linker predominantly led to NMDAR gain-of-function, while misATD+LBD exclusively caused NMDAR loss-of-function. With respect to null variants, we show that Grin2a+/- cortical rat neurons also had reduced NMDAR function and there was no evidence of previously postulated compensatory overexpression of GluN2B. We demonstrate that null variants and misATD+LBD of GRIN2A do not only share the same clinical spectrum (i.e. milder phenotypes), but also result in similar electrophysiological consequences (loss-of-function) opposing those of misTMD+Linker (severe phenotypes; predominantly gain-of-function). This new pathomechanistic model may ultimately help in predicting phenotype severity as well as eligibility for potential precision medicine approaches in GRIN2A-related disorders

Sleep disorders and ADHD symptoms in children and adolescents with typical absence seizures: An observational study

International audienceObjective: To assess the occurrence of sleep disorders (SD) and attention deficit hyperactivity disorder (ADHD) symptoms in children with typical absence seizures (TAS) compared to control children and to evaluate the impact of epilepsy-related factors on sleep and attention in children with TAS.Methods: The Sleep Disturbance Scale for Children (SDSC) and the ADHD rating scale were filled in by parents of a cohort composed by 82 children aged from 5 to 15.6 years, 49% of boys (41 with TAS with a syndromic diagnosis of childhood absence epilepsy and 41 controls). For children with TAS, the Pediatric Epilepsy Side Effects Questionnaire was completed. Statistical analyses were conducted in order to compare sleep and attention scores between groups. In children with TAS, a correlation was computed between these scores. Logistics regression models were conducted to identify predictors of excessive diurnal sleepiness and inattention in children with TAS.Results: Compared to controls, children with TAS had higher total scores for subjective sleep (mean 42.9 vs 38.3, p = 0.05) and attention disorders (mean 16.8 vs 11.6, p = 0.01), especially for excessive diurnal sleepiness (mean 3.9 vs 3.2, p = 0.02) and inattention (mean 9.3 vs 5.6, p = 0.003) components. In children with TAS, sleep problems were significantly under-reported by parents. Sleep disorders symptoms as breathing-related sleep disturbance, excessive diurnal sleepiness or naps at or after 7 years of age were reported. Subjective sleep and attention disorders were significantly correlated (r = 0.43, p = 0.01). Subjective excessive diurnal sleepiness may be the result of a polytherapy (p = 0.05) or a side effect of anti-seizure medication (ASM) (p = 0.03) but children without medication side effects also reported subjective SD. In children with TAS, the risk of inattention symptoms was increased in boys (p = 0.02), with a high BMI (p = 0.05), or with ASM side effects (p = 0.03).Conclusions: This study demonstrates that children with TAS are at risk of sleep and attention disorder symptoms. If attention disorders in a context of epilepsy are now widely assessed and identified, sleep disorders are still under-estimated. An accurate identification and management of sleep disorders could improve academic performances, quality of life, and seizure management in children with TAS

Ring 14 chromosome presenting as early-onset isolated partial epilepsy.

International audienceWe report four infants (two males, two females) with ring 14 chromosome presenting with early-onset partial epilepsy. The first seizure occurred between 3 and 6 months (3, 3, 4, and 6mo respectively). In all four cases, diagnosis was based on early focal seizures, rather than on psychomotor retardation or morphological features, which were not prominent at seizure onset. Moreover, despite the young age of the patients and the high frequency of seizures, neither epileptic spasms nor progression to 'epileptic encephalopathy', such as hypsarrhythmia, were observed. Epilepsy remained partial in these patients. At the most recent follow-up, all four children had slight or mild psychomotor delay, and two of them had moderate non-specific dysmorphic traits. Data from the literature about epilepsy in ring 14 chromosome syndrome were also reviewed. Ring 14 chromosome syndrome may be revealed by isolated, early-onset focal epilepsy suggestive of focal lesions with only mild mental retardation and morphological features at the time of diagnosis. The characteristics of these observations differ from classic ring 14 syndrome, and may enlarge this clinical spectrum. Many unanswered questions remain concerning phenotype-genotype correlation and identification of the potential genes and molecular mechanisms responsible for epilepsy in patients with ring 14 syndrome

Homozygous TBC1D24 mutation in two siblings with familial infantile myoclonic epilepsy (FIME) and moderate intellectual disability

International audienceMutations in the TBC1D24 gene were first reported in an Italian family with a unique epileptic phenotype consisting of drug-responsive, early-onset idiopathic myoclonic seizures. Patients presented with isolated bilateral or focal myoclonia, which could evolve to long-lasting attacks without loss of consciousness, with a peculiar reflex component, and were associated with generalized tonic—clonic seizures. This entity was named ''familial infantile myoclonic epilepsy'' (FIME). More recently, TBC1D24 mutations have been shown to cause a variable range of disorders, including epilepsy of various seizure types and severity, non-syndromic deafness, and DOORS syndrome. We report on the electro-clinical features of two brothers, born to first-cousin parents, affected with infantile-onset myoclonic epilepsy. The peculiar epileptic presentation prompted us to perform direct sequencing of the TBC1D24 gene. The patients had very early onset of focal myoclonic fits with variable topography, lasting a few minutes to several hours, without loss of consciousness, which frequently evolved to generalized myoclonus or myoclonic status. Reflex myoclonia were noticed in one patient. Neurological outcome was marked by moderate intellectual disability. Despite the high frequency of seizures, repeated EEG recordings showed normal background rhythm and rare interictal spikes and waves. We found a homozygous missense mutation , c.457G>A/p.Glu153Lys, in the two affected brothers. This observation combined with recent data from the literature, suggest that mutations in TBCD24 cause a pathological continuum, with FIME at the ''benign'' end and severe drug-refractory epileptic encephalopathy on the severe end. Early-onset myoclonic epilepsy with focal and generalized myoclonic seizures is a common characteristic of this continuum

Infantile-Onset Paroxysmal Movement Disorder and Episodic Ataxia Associated with a TBC1D24 Mutation

Mutations that disrupt the TBC1D24 presynaptic protein have been implicated in various neurological disorders including epilepsy, chronic encephalopathy, DOORS (deafness, onychodystrophy, osteodystrophy, mental retardation, and seizures) syndrome, nonsyndromic hearing loss, and myoclonus. We present the case of a 22-month-old male with infantile-onset paroxysmal episodes of facial and limb myoclonus. The episodes were linked to biallelic variants in exon 2 of the TBC1D24 gene that lead to amino acid changes (c.304C >T/p.Pro102Ser and c.410T > C/p.Val137Ala), each variant being inherited from a parent. Follow-up imaging in adolescence revealed widened right cerebellar sulci. We discuss the evolving landscape of TBC1D24 associated phenotypes; this case adds to a growing body of evidence linking this gene to movement disorders in children

Intrainsular functional connectivity in human

Objectives: The anatomical organization of the insular cortex is characterized by its rich and heterogeneous cytoarchitecture and its wide network of connections. However, only limited knowledge is available regarding the intrainsular connections subserving the complex integrative role of the insular cortex. The aim of this study was to analyze the functional connectivity within-and across-insular subregions, at both gyral and functional levels. Experimental design: We performed intracerebral electrical stimulation in 10 patients with refractory epilepsy investigated with depth electrodes, 38 of which were inserted in the insula. Bipolar electrical stimulation, consisting of two series of 20 pulses of 1-ms duration, 0.2-Hz frequency, and 1-mA intensity, was delivered at each insular contact. For each stimulated insular anatomical region, we calculated a rate of connectivity, reflecting the proportion of other insular contacts, showing significant evoked potentials. Results: Statistically significant evoked potentials were recorded in 74% of tested connections, with an average latency of 26 6 3 ms. All insular gyri were interconnected, except the anterior and posterior short gyri. Most connections were reciprocal, showing no clear anterior to posterior directionality. No connection was observed between the right and the left insula. Conclusions: These findings point to specific features of human insula connectivity as compared to non-Human primates, and remain consistent with the complex integration role devoted to the human insula in many cognitive domains

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 6 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

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 6 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