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We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease., (Copyright © 2019 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy., (Copyright © 2017 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Epileptic encephalopathies are increasingly thought to be of genetic origin, although the exact etiology remains uncertain in many cases. We describe here three girls from two nonconsanguineous families affected by a clinical entity characterized by dysmorphic features, early-onset intractable epilepsy, intellectual disability, and cortical blindness. In individuals from each family, brain imaging also showed specific changes, including an abnormally marked pontobulbar sulcus and abnormal signals (T2 hyperintensities) and atrophy in the occipital lobe. Exome sequencing performed in the first family did not reveal any gene with rare homozygous variants shared by both affected siblings. It did, however, show one gene, DOCK7, with two rare heterozygous variants (c.2510delA [p.Asp837Alafs(∗)48] and c.3709C>T [p.Arg1237(∗)]) found in both affected sisters. Exome sequencing performed in the proband of the second family also showed the presence of two rare heterozygous variants (c.983C>G [p.Ser328(∗)] and c.6232G>T [p.Glu2078(∗)]) in DOCK7. Sanger sequencing confirmed that all three individuals are compound heterozygotes for these truncating mutations in DOCK7. These mutations have not been observed in public SNP databases and are predicted to abolish domains critical for DOCK7 function. DOCK7 codes for a Rac guanine nucleotide exchange factor that has been implicated in the genesis and polarization of newborn pyramidal neurons and in the morphological differentiation of GABAergic interneurons in the developing cortex. All together, these observations suggest that loss of DOCK7 function causes a syndromic form of epileptic encephalopathy by affecting multiple neuronal processes., (Copyright © 2014 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)

Epilepsy surgery is now accepted as a well proven therapeutic strategy for resistant epileptic patients either adults or children. Even though investigations and surgical techniques are similar in both groups, epileptic surgery in paediatric patients has some particularities. Epileptic aetiologies can differ in children, the disease occurs in an immature brain, at a time of intense plasticity, especially in younger patients. When treating a paediatric epileptic patient, one must not only consider seizure control but also cognitive, social and behavioural developments. Surgery should be considered in all patients with refractory epilepsy and potential candidates to surgery should be oriented to a specialized center, where a multimodal and multidisciplinary workup is available, allowing to determine if surgery is to be considered, depending on the results.

Hemimegalencephaly is a rare congenital brain malformation, usually associated with mental retardation, * refractory epilepsy, and progressive neurological deficits. We report the case of a 19-year-old female with de novo diagnosis of right hemimegalencephaly, normal intellectual function, and history of non-refractory epilepsy. She presented with weakness and paraesthesia of the left leg. Extensive evaluation was negative for other causes for the weakness, which was attributed to progressive neurological damage secondary to long-standing subclinical epileptic activity in the hemimegalencephalic hemisphere. This patient underwent a cerebral fluorodeoxyglucose positron emission tomography that demonstrated near-normal cortical metabolism. Formal neuropsychological evaluation revealed mild deficits in the affected hemisphere, but preserved general intellectual function. This case illustrates the wide phenotypic variations in this condition and raises questions about prenatal counselling for hemimegalencephaly., (© The Authors. Developmental Medicine & Child Neurology © 2011 Mac Keith Press.)

We sequenced genes coding for components of the SNARE complex (STX1A, VAMP2, SNAP25) and their regulatory proteins (STXBP1/Munc18-1, SYT1), which are essential for neurotransmission, in 95 patients with idiopathic mental retardation. We identified de novo mutations in STXBP1 (nonsense, p.R388X; splicing, c.169+1G>A) in two patients with severe mental retardation and nonsyndromic epilepsy. Reverse transcriptase polymerase chain reaction and sequencing showed that the splicing mutation creates a stop codon downstream of exon-3. No de novo or deleterious mutations in STXBP1 were found in 190 control subjects, or in 142 autistic patients. These results suggest that STXBP1 disruption is associated with autosomal dominant mental retardation and nonsyndromic epilepsy.

Object: Ischemic cerebral vascular accidents (CVAs) in children result in epilepsy in 25% of patients, which is refractory in 7% of cases. Repeated seizures worsen the global and cognitive prognosis of these patients. To evaluate the prognosis of epilepsy and cognitive development in children with refractory seizures following a CVA, the authors retrospectively studied the effectiveness of periinsular hemispherotomy in the treatment of these patients., Methods: Between March 1995 and November 2007, 8 children who suffered from stroke-induced refractory epilepsy underwent a periinsular hemispherotomy. All patients' charts were reviewed in a retrospective manner. Age at the time of the CVA, imaging studies, cause of the ischemic event, onset of the first seizure, patient's handedness, the extent of the parenchymal damage, electroencephalography findings, type of epileptic seizures, number of seizures per day, number of antiepileptic medications, preoperative neuropsychological evaluation, and surgical outcome with regard to the patient's seizure activity were analyzed., Results: There were 7 boys and 1 girl in this study. The mean age at stroke was 23 months (range birth-5 years). The mean age at onset of epilepsy was 22 months (range 0-60 months). The mean age at the time of the hemispherotomy was 7 years (range 54-130 months). The average delay prior to the hemispherotomy was 5 years and 3 months (range 23-115 months). Prior to surgery, the average number of seizures per day was 35 (range 5-100). The average number of antiepileptic medications introduced before the hemispherotomy was 8 (range 6-12). Six patients required only 1 surgical intervention and 2 necessitated 2 separate operations:1 underwent a 2-staged hemispherotomy and the other underwent a prior callosotomy. There were no reported surgical complications in this series. Seven children are seizure free. However, the remaining child, after a 3.5-year disease-free interval, has recently started having seizures. No child demonstrated an improvement in neuropsychological evaluation., Conclusions: The periinsular hemispherotomy must be considered an alternative in the therapeutic approach to stroke-induced pediatric refractory epilepsy. It is effective in controlling seizure activity. The authors believe the delay before hemispherotomy must be shortened in children with post-CVA refractory epilepsy.

The intracarotid amobarbital test (IAT) is the most widely used procedure for pre-surgical evaluation of language lateralization in epileptic patients. However, apart from being invasive, this technique is not applicable in young children or patients who present mental retardation and/or language deficits. Functional magnetic resonance imaging (fMRI) is increasingly employed as a non-invasive alternative. Again, this method is more difficult to use with young children, especially hyperactive ones, since they have to remain motionless during data acquisition. The aim of this study was to determine whether near-infrared spectroscopy (NIRS) can be used as an alternative technique to investigate language lateralization in children and special populations. Unlike Wada test, NIRS is non-invasive, and it is more tolerant to movement artefacts than fMRI. In the present study, NIRS data were acquired in four epileptic children, a 12-year-old boy with pervasive developmental disorder and a 3-year-old, healthy child, as well as three healthy and two epileptic adults, while they performed a verbal fluency task and a control task. When applicable, the results were compared to the subjects' fMRI and/or IAT findings. Clear laterality of speech was obtained in all participants, including the two non-epileptic children, and NIRS results matched fMRI and IAT findings. These results, if replicable in larger samples, are encouraging and suggest that NIRS has the potential to become a viable, non-invasive alternative to IAT and fMRI in the determination of speech lateralization in children and clinical populations that cannot be submitted to more invasive techniques.

Objective: The high-fat ketogenic diet has long been used to treat refractory childhood seizures, but whether there is a relation between the degree of ketosis and effectiveness of seizure control remains unclear. Frequent measurements of plasma ketones are difficult in children so the goal was to determine the utility of breath acetone as a marker of systemic ketosis and seizure control in children given the ketogenic diet because of seizures refractory to medication., Methods: In experiment I, breath acetone and plasma ketones were assessed every 2 h during an 8-h test day in seven children. In experiment II, a preliminary assessment of the possible relation between breath acetone and seizure frequency was made over 14 d in five children and one adolescent on the ketogenic diet., Results: Breath acetone was positively and curvilinearly related to plasma acetone (r2 = 0.99, P < 0.0001), plasma acetoacetate (r2 = 0.89, P < 0.0001), and plasma beta-hydroxybutyrate (r2 = 0.94, P < 0.0001). No significant relation was found between breath acetone and seizure frequency or change in seizure frequency., Conclusions: Breath acetone is indicative of systemic ketosis while on the ketogenic diet. However, owing to the wide range of seizure types and plasma acetone, more subjects will be needed to determine whether there is a clear link between breath acetone and seizure frequency or decreased seizure frequency while on the high-fat ketogenic diet.

Purpose: To assess the influence of the family history (FH) of epilepsy or febrile seizures (FSs) on the clinical presentation of FSs and on their outcome., Methods: We reviewed the charts of 482 children admitted to the Ste-Justine Hospital with FSs between 3 months and 6 years of age and followed for at least 5 years., Results: Children with a positive FH of epilepsy (n=67) showed significantly more focal and recurrent FSs than those without such a FH. The risk of developing partial epilepsy (n=17) or generalized epilepsy (n=19) was significantly greater in children with focal or recurrent FSs, respectively. In children with focal FSs, only two out of 30 (6.7%) children with a negative FH of epilepsy developed partial epilepsy compared with four out of nine (44.4%) children with a positive FH. In children with recurrent FSs, as much as seven out of 34 (20.6%) children with a positive FH of epilepsy developed generalized epilepsy compared to only eight out of 161 (0.05%) of those with a negative FH. Nevertheless, when not taking into account the clinical presentation of FSs, the positive FH of epilepsy constituted a risk factor for developing generalized but not partial epilepsy. Finally, children with a positive FH of FSs (n=120) exhibited significantly more recurrent FSs than those without such a FH, but this did not modify the risk of epilepsy., Conclusion: The FH of FSs and/or epilepsy should be taken into account when evaluating the risk of FSs recurrence and of epilepsy.

To describe the poorly known characteristics of epilepsy during infancy in focal cortical dysplasia (FCD), one of the most frequent cause of infantile epilepsy. All 28 patients with FCD referred to two specialized centres were retrospectively studied regarding seizure characteristics, psychomotor evaluation, and response to medical and surgical treatment. All patients presented with early partial seizures. Semiology, but not the age of onset, depended on the topography of the dysplasia, with abnormal eye movements in all cases of posterior FCD. Eleven patients also developed infantile spasms (IS), mainly asymmetrical. IS were easily controlled with Vigabatrin or ACTH, but no partial seizures could be medically controlled except in one patient. All patients except one had abnormal neuropsychological findings. Fifteen patients had surgery, eight became seizure free, and seven were significantly improved regarding psychomotor development. Very early and refractory partial seizures, but easily controlled IS are the main characteristics of FCD in infancy. Only the focal ictal semiology may help differentiate the localization of FCD. Its intrinsic epileptogenicity could sustain this clinical pattern. Since the chances for medical control and normal neurodevelopment are poor, surgical treatment should be considered early in infants with FCD., (Copyright 2002 Elsevier Science B.V.)

Introduction: Pediatric frontal and temporal lobe epilepsies (FLE, TLE) have been associated with language impairments and structural and functional brain alterations. However, there is no clear consensus regarding the specific patterns of cerebral reorganization of language networks in these patients. The current study aims at characterizing the cerebral language networks in children with FLE or TLE, and the association between brain network characteristics and cognitive abilities. Methods: Twenty (20) children with FLE or TLE aged between 6 and 18 years and 29 age- and sex-matched healthy controls underwent a neuropsychological evaluation and a simultaneous functional near-infrared spectroscopy and electroencephalography (fNIRS-EEG) recording at rest and during a receptive language task. EEG was used to identify potential subclinical seizures in patients. We removed these time intervals from the fNIRS signal to investigate language brain networks and not epileptogenic networks. Functional connectivity matrices on fNIRS oxy-hemoglobin concentration changes were computed using cross-correlations between all channels. Results and discussion: Group comparisons of residual matrices (=individual task-based matrix minus individual resting-state matrix) revealed significantly reduced connectivity within the left and between hemispheres, increased connectivity within the right hemisphere and higher right hemispheric local efficiency for the epilepsy group compared to the control group. The epilepsy group had significantly lower cognitive performance in all domains compared to their healthy peers. Epilepsy patients' local network efficiency in the left hemisphere was negatively associated with the estimated IQ (p = 0.014), suggesting that brain reorganization in response to FLE and TLE does not allow for an optimal cognitive development. [ABSTRACT FROM AUTHOR]

Aim: To evaluate clinicians' and patients' perceptions of pharmacogenetic testing in a clinical setting. Materials & methods: This is a pragmatic mixed-method prospective observational study. Hospital pharmacists and neurologists participated in focus groups regarding pharmacogenetic testing; patients who received pharmacogenetic testing and their community pharmacists completed surveys to assess their perception of these tests. Results: Most study participants had a positive view of pharmacogenetic testing. Three major themes were identified from the focus groups: receptiveness to pharmacogenetic testing, pharmacogenetic test characteristics and integrating pharmacogenetic tests into practice. Conclusion: The views reported are encouraging for the eventual implementation of pharmacogenetics in practice. Local integration of these tests is an essential step to improve patient care through personalized medicine. Genetic tests can help predict patients' response to medication. This study aimed to evaluate clinicians' and patients' perceptions of these genetic tests. Pediatric patients, with epilepsy, were tested and completed a survey to assess their perception of these tests. A survey was also completed by their community pharmacists, and virtual discussion groups were held with hospital pharmacists and neurologists. Most participants had a positive view of these tests, with three major themes identified from the discussion groups: receptiveness to testing, test characteristics and integration of tests into practice. The views reported are encouraging for the eventual implementation of these tests in practice, an essential step to improve patient care through personalized medicine. A pragmatic mixed-methods prospective observational study found that clinicians and patients favor the implementation of pharmacogenetic testing in the field of pediatric epilepsy to improve patient care #pharmacogenetics #pediatric #neurology. [ABSTRACT FROM AUTHOR]

Several specific syndromes within the RASopathies spectrum lead to an increased risk of seizures up to developing refractory epileptic encephalopathy. Management remains symptomatic. Here we report two patients treated with trametinib, a MEK1-2 inhibitor, as a precision strategy for drug-resistant epilepsy. Patient 1 is a six-year-old girl with cardiofaciocutaneous syndrome (BRAF p.F595L, germline mutation), and Patient 2 is a 14-month-old boy with Schimmelpenning syndrome (KRAS p.G12D, postzygotic somatic mutation). Trametinib was initiated at a dosage of 0.025 mg/kg/day. Patient 1 had multiple seizures per day, multifocal motor to bilateral tonic-clonic. Electroencephalography (EEG) showed a dramatic reduction in EEG discharges three months after trametinib onset, while a marked clinical improvement occurred after about five months, at the same dosage, and the girl is currently seizure-free for more than six months. Patient 2 had left cerebral hemiatrophy leading to right focal motor seizures, multiple per week to multiple per day, since the age of three months. On trametinib, he experienced an early benefit, remaining seizure-free for more than three months. However, after six months we observed recurrence of seizures. After 22 months of treatment, trametinib was discontinued because of a suspected drug-induced inflammatory colitis. After discontinuation, we observed a significant clinical and EEG "rebound effect." We provide proof of concept that MEK inhibition is a promising approach for the treatment of patients with refractory epilepsy with selected germline and mosaic RASopathies. Future trials are encouraged to better investigate their potentials and limitations. [ABSTRACT FROM AUTHOR]

Epilepsy is a heterogeneous neurological disease affecting approximately 50 million people worldwide. Genetic factors play an important role in both the onset and severity of the condition, with mutations in several ion‐channel genes being implicated, including those encoding the GABAA receptor. Here, we evaluated the frequency of additional mutations in the GABAA receptor by direct sequencing of the complete open reading frame of the GABRA1 and GABRG2 genes from a cohort of French Canadian families with idiopathic generalized epilepsy (IGE). Using this approach, we have identified three novel mutations that were absent in over 400 control chromosomes. In GABRA1, two mutations were found, with the first being a 25‐bp insertion that was associated with intron retention (i.e. K353delins18X) and the second corresponding to a single point mutation that replaced the aspartate 219 residue with an asparagine (i.e. D219N). Electrophysiological analysis revealed that K353delins18X and D219N altered GABAA receptor function by reducing the total surface expression of mature protein and/or by curtailing neurotransmitter effectiveness. Both defects would be expected to have a detrimental effect on inhibitory control of neuronal circuits. In contrast, the single point mutation identified in the GABRG2 gene, namely P83S, was indistinguishable from the wildtype subunit in terms of surface expression and functionality. This finding was all the more intriguing as the mutation exhibited a high degree of penetrance in three generations of one French Canadian family. Further experimentation will be required to understand how this mutation contributes to the occurrence of IGE in these individuals. [ABSTRACT FROM AUTHOR]

The phenotypic and etiologic spectrum in adults with nodular heterotopias (NHs) has been well characterized. However, there are no large pediatric case series. We, therefore, wanted to review the clinical features of NHs in our population. Hospital records of 31 patients with pathology or imaging-confirmed NHs were reviewed. Two-sided Fisher's exact t-test was used to assess associations between distribution of NHs and specific clinical features. NHs were distributed as follows: 8 (26%) unilateral focal subependymal, 3 (10%) unilateral diffuse subependymal, 5 (16%) bilateral focal subependymal, 12 (39%) bilateral diffuse subependymal, and 3 (10%) isolated subcortical. The phenotypic spectrum in our population differs from that described in adults. Significant morbidity and mortality are associated with presentation in childhood. Twenty-two of 31 patients (71%) died in the neonatal period or in childhood. Additional cerebral malformations were found in 80% and systemic malformations in 74%. The majority of patients had developmental delay, intellectual deficit, and intractable epilepsy. Patients with unilateral focal NHs were more likely to have ventriculomegaly (p = 0.027), and those with bilateral diffuse NHs more likely to have cerebellar abnormalities (p = 0.007). Isolated subcortical NHs were associated with multiple malformations (p = 0.049) and cardiac abnormalities (p = 0.027). Underlying etiology was heterogeneous and determined in only six cases (19%): del chr 1p36, del chr 15q11, pyruvate dehydrogenase deficiency, sialic acidosis type 1, Aicardi syndrome, and FLNA mutation. NHs are present in childhood as part of multiple cerebral and systemic malformations; developmental delay and refractory seizures are the rule rather than the exception. Milder forms go unrecognized until seizure onset in adulthood. [ABSTRACT FROM AUTHOR]

We present two methods of implantation for the investigation of suspected insular and perisylvian epilepsy that combine depth and subdural electrodes to capitalize on the advantages of each technique. Retrospective study of all intracranial EEG studies that included insular electrodes from 2004-2010. Patients were divided according to the implantation scheme. The first method (type 1) consisted of a craniotomy, insertion of insular electrodes after microdissection of the sylvian fissure, orthogonal implantation of mesiotemporal structures with neuronavigation, and coverage of the adjacent lobes with subdural electrodes. The second method (type 2) consisted of magnetic resonance imaging (MRI)-stereotactic frame-guided depth electrode implantation into insula and hippocampus using sagittal axes, and insertion of subdural electrodes through burr holes to cover the adjacent lobes. The combined implantations were developed and performed by one neurosurgeon (AB). Nineteen patients had an intracranial study that sampled the insula, among other regions. Sixteen patients were implanted using the first method, which allowed a mean of 4, 5, 20, 15, and 42 contacts per patient to be positioned into/over the insular, mesial temporal, neocortical temporal, parietal, and frontal areas, respectively. The second method (three patients) allowed a mean of 8, 7, 16, 6, and 9 contacts per patient to sample the same areas, respectively. The four patients in whom transient neurologic deficits occurred were investigated with use of type 1 implantation. Combined depth and subdural electrodes can be used safely to investigate complex insular/perisylvian refractory epilepsy. Choice of implantation scheme should be individualized according to presurgical data and the need for functional localization. [ABSTRACT FROM AUTHOR]

Abstract: Purpose: The goal of this retrospective study is to review the causes of infantile spasms and to correlate aetiology with outcome. Methods: All children diagnosed with infantile spasms between 1990 and 2003 at our institution were included. Charts were reviewed for the presence or absence of a defined aetiology/association, response to treatment, long-term epileptic and cognitive outcome. Results: 80 out of 95 children are included in this review. 50 children (63%) had symptomatic spasms with disorders of cortical development being the most frequent cause followed by neonatal injury and tuberous sclerosis. Symptomatic children with developmental brain lesions responded at a rate of 54% to vigabatrin versus 62% for ACTH/prednisone, while other symptomatic aetiologies 83% responded to vigabatrin versus 63% for ACTH/prednisone. Cryptogenic spasms responded at a similar rate to both drugs. Other than children with cryptogenic spasms, very few went on to develop normally. Our results are however biased by on average more than 30 days of delay to diagnosis. None of our children developed Lennox-Gastaut syndrome but a number developed severe epilepsy with multifocal spikes. Discussion: The aetiology and prognosis of infantile spasms is evolving. To improve outcome, we need to reduce the delay to diagnosis and develop prospective double-blind randomized clinical trials looking at not only the epileptic outcome but also cognitive outcome of these children. [Copyright &y& Elsevier]

Gamma band electroencephalography (EEG) abnormalities have been reported in patients with epilepsy. We aimed to investigate whether patients with febrile seizures (FS) show abnormalities of the gamma frequency steady-state visual evoked potential (SSVEP) components evoked by intermittent photic stimulation (IPS). We analyzed the magnitude and phase alignment of the 50–100 Hz SSVEP components elicited by IPS from 12 FS patients, 5 siblings of FS patients, and 15 control children between 6 and 36 months of age. Patients with FS showed significantly higher SSVEP magnitude and phase alignment values when compared to both the siblings and control groups. Detected abnormalities could either represent the direct consequence of seizures or indicate a preexisting tendency to hypersynchrony in FS patients. Future prospective studies could assess whether SSVEP abnormalities are associated with complex rather than simple FS, or have a prognostic value for the development of epilepsy following FS. [ABSTRACT FROM AUTHOR]

Rationale: Few studies have looked at long-term epileptic and cognitive outcome of frontal lobe epilepsy (FLE) in children. Most are limited by inclusion of lesional and nonlesional patients. Goal: To define the epileptic and functional outcome of children with nonlesional FLE. Methods: We reviewed medical records and neuropsychological evaluations of patients with nonlesional FLE diagnosed between 1994 and 2004. We included children with either focal or regional frontal EEG and/or functional imaging abnormalities. We reviewed their charts for seizure and neuropsychological outcome. Results: We included 21 children. Twelve (57.1%) presented with daily seizures. Seizures were nocturnal in 8 of 21, secondarily generalized in 6 of 21, adversive in 5 of 21, and focal motor in 6 of 21. Although, initial seizure control was poor in 14 of 21, long-term control was achieved in 10 of 21 after 14.6 ± 22.3 months. Early development was normal in 12 of 21 but at later formal neuropsychological evaluation only 3 of 12 still had a normal profile. The majority of children had learning difficulties requiring special education prior to seizure onset (6 of 10). A clearly defined regression after seizure onset was observed in three children. The majority exhibited attention deficit and hyperactivity or impulsivity (14 of 21), behavioral problems (8 of 21), and cognitive impairments (10 of 21). Early seizure control was associated with a better cognitive outcome. Conclusion: Nonlesional FLE is associated with poor seizure and behavioral outcomes. Whether this is secondary to MRI-silent developmental lesions or to the progressive repercussion of seizures on frontal lobe functions remains uncertain. A prospective study with early neuropsychological assessment could help confirm the latter. [ABSTRACT FROM AUTHOR]

Although many genes that predispose for epilepsy in humans have been determined, those that underlie the classical syndromes of idiopathic generalized epilepsy (IGE) have yet to be identified. We report that an Ala322Asp mutation in GABRA1, encoding the α1 subunit of the γ-aminobutyric acid receptor subtype A (GABA[sub A]), is found in affected individuals of a large French Canadian family with juvenile myoclonic epilepsy. Compared with wildtype receptors, GABA[sub A] receptors that contain the mutant subunit show a lesser amplitude of GABA-activated currents in vitro, indicating that seizures may result from loss of function of this inhibitory ligand-gated channel. Our results confirm that mutation of GABRA1 predisposes towards a common idiopathic generalized epilepsy syndrome in humans. [ABSTRACT FROM AUTHOR]

STXBP1 (Munc18-1) is a component of the machinery involved in the fusion of secretory vesicles to the presynaptic membrane for the release of neurotransmitters. De novo missense mutations in STXBP1 were recently reported in patients with Ohtahara syndrome, a form of encephalopathy with severe early-onset epilepsy. In addition, sequencing of the coding region of STXBP1 in 95 patients with non-syndromic intellectual disability (NSID) revealed de novo truncating mutations in two patients who also showed severe non-specific epilepsy, suggesting that STXBP1 disruption has the potential of causing a wide spectrum of epileptic disorders in association with intellectual disability. Here, we report on the mutational screening of STXBP1 in a different series of 50 patients with NSID and the identification of a novel de novo truncating mutation (c.1206delT/ p.Y402X) in a male with NSID, but surprisingly with no history of epilepsy. This is the first report of a patient with a truncating mutation in STXBP1 that does not show epilepsy, thus, expanding the clinical spectrum associated with STXBP1 disruption. [ABSTRACT FROM AUTHOR]

Background: Seizures are one of the most common symptoms of pediatric brain tumors. The purpose of this study was to define seizures related to primary central nervous system tumors and to identify risk factors predictive of seizure occurrence and recurrence.Methods: We reviewed the records of children treated from January 1, 2004, to January 1, 2018 and collected data including age, gender, tumor location, histology, extent of initial resection, seizure characteristics, treatment modalities, recurrence, and seizure control. A binomial logistic regression was performed to determine the risk factors of seizure occurrence.Results: During the observation period, 348 children were diagnosed with a primary brain tumor. The median age at diagnosis was 7.8 years, and the median follow-up interval was 3.9 years. There were 196 boys (56.3%). In our cohort, a total of 70 children (20.1%) experienced seizures. Most of them (64.3%) had cortical tumors. All patients with dysembryoplastic neuroepithelial tumors and 81.8% of patients with glioneuronal tumors presented seizures. Risk factors associated with an increased risk for seizures included cortical location, tumor recurrence, and age at diagnosis. Thirty-nine (86.7%) patients with seizures at diagnosis were seizure free at last follow-up (Engel 1). Significantly more patients (69.6%) with a gross total resection were withdrawn from their antiepileptic drugs when compared with those with subtotal resection (27.3%, P = 0.007).Conclusions: Our study is the largest cohort in children with tumor-related seizures and brings new insight in terms of seizure risk according to tumor types and evolution following treatment. [ABSTRACT FROM AUTHOR]