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We report detailed functional analyses and genotype-phenotype correlations in 392 individuals carrying disease-causing variants in SCN8A, encoding the voltage-gated Na+ channel Nav1.6, with the aim of describing clinical phenotypes related to functional effects. Six different clinical subgroups were identified: Group 1, benign familial infantile epilepsy (n = 15, normal cognition, treatable seizures); Group 2, intermediate epilepsy (n = 33, mild intellectual disability, partially pharmaco-responsive); Group 3, developmental and epileptic encephalopathy (n = 177, severe intellectual disability, majority pharmaco-resistant); Group 4, generalized epilepsy (n = 20, mild to moderate intellectual disability, frequently with absence seizures); Group 5, unclassifiable epilepsy (n = 127); and Group 6, neurodevelopmental disorder without epilepsy (n = 20, mild to moderate intellectual disability). Those in Groups 1–3 presented with focal or multifocal seizures (median age of onset: 4 months) and focal epileptiform discharges, whereas the onset of seizures in patients with generalized epilepsy was later (median: 42 months) with generalized epileptiform discharges. We performed functional studies expressing missense variants in ND7/23 neuroblastoma cells and primary neuronal cultures using recombinant tetrodotoxin-insensitive human Nav1.6 channels and whole-cell patch-clamping. Two variants causing developmental and epileptic encephalopathy showed a strong gain-of-function (hyperpolarizing shift of steady-state activation, strongly increased neuronal firing rate) and one variant causing benign familial infantile epilepsy or intermediate epilepsy showed a mild gain-of-function (defective fast inactivation, less increased firing). In contrast, all three variants causing generalized epilepsy induced a loss-of-function (reduced current amplitudes, depolarizing shift of steady-state activation, reduced neuronal firing). Functional effects were known for 170 individuals. All 136 individuals carrying a functionally tested gain-of-function variant had either focal (n = 97, Groups 1–3) or unclassifiable (n = 39) epilepsy, whereas 34 individuals with a loss-of-function variant had either generalized (n = 14), no (n = 11) or unclassifiable (n = 6) epilepsy; only three had developmental and epileptic encephalopathy. Computational modelling in the gain-of-function group revealed a significant correlation between the severity of the electrophysiological and clinical phenotypes. Gain-of-function variant carriers responded significantly better to sodium channel blockers than to other anti-seizure medications, and the same applied for all individuals in Groups 1–3. In conclusion, our data reveal clear genotype-phenotype correlations between age at seizure onset, type of epilepsy and gain- or loss-of-function effects of SCN8A variants. Generalized epilepsy with absence seizures is the main epilepsy phenotype of loss-of-function variant carriers and the extent of the electrophysiological dysfunction of the gain-of-function variants is a main determinant of the severity of the clinical phenotype in focal epilepsies. Our pharmacological data indicate that sodium channel blockers present a treatment option in SCN8A-related focal epilepsy with onset in the first year of life.

Dravet syndrome (DS) is a monogenic syndrome associated with SCN1A mutations in the majority of patients and characterized by devastating epilepsy, that may be life-threatening. Aside from refractory seizures, core symptoms of DS include behavioral difficulties, developmental delay, cognitive impairment, and motor dysfunction. Previous DS research has mainly focused on epileptic seizures and pharmacological management and less on behavioral difficulties. This study aims to explore the lived experience of parents supporting a child with DS, with a focus on behavioral aspects.We performed a qualitative study using focus groups and following the consolidated criteria for reporting qualitative research (COREQ) guidelines. We organized three focus groups with parents of children and adults with DS and used a pre-defined topic list of open questions, similar for each focus group to ensure comparability. The focus groups were video recorded, transcribed, and anonymized. Data were analyzed using an iterative coding process where codes were sorted into themes. Differences in coding among the researchers were discussed until a consensus was reached.In total, twenty parents (mothers only) participated in the study. The age of children with DS ranged between 3 to 22 years with a mean age of 11.8 years. A range of behavioral difficulties emerged from the thematic analysis. Overall, the most commonly mentioned behavioral difficulties were aggression, dangerous behavior, impulsivity, hyperactivity, routinized and compulsive habits. Our results showed different behavior per age group, with more externalizing behaviors such as aggression and impulsivity in children aged 3-13 years; and more internalizing behavior such as routinized and compulsive habits in adolescents and young adults (14-22 years). This results in a different kind of support these families need and should be acknowledged when in consult with a healthcare professional. Parents reported that challenging behavior was a source of stress and impacted negatively on their family's quality of life. Parents reported feeling alone in their search for solutions, and many explored options outside the traditional medical context.Our results suggest that the challenging behavior associated with DS leads to a huge burden of care. Healthcare professionals working with DS patients may need to develop shared decision-making strategies that take into account challenging behavior.

CSNK2B has recently been implicated as a disease gene for neurodevelopmental disability (NDD) and epilepsy. Information about developmental outcomes has been limited by the young age and short follow-up for many of the previously reported cases, and further delineation of the spectrum of associated phenotypes is needed. We present 25 new patients with variants in CSNK2B and refine the associated NDD and epilepsy phenotypes. CSNK2B variants were identified by research or clinical exome sequencing, and investigators from different centers were connected via GeneMatcher. Most individuals had developmental delay and generalized epilepsy with onset in the first 2 years. However, we found a broad spectrum of phenotypic severity, ranging from early normal development with pharmacoresponsive seizures to profound intellectual disability with intractable epilepsy and recurrent refractory status epilepticus. These findings suggest that CSNK2B should be considered in the diagnostic evaluation of patients with a broad range of NDD with treatable or intractable seizures.

Genetic testing and counselling are increasingly important in epilepsy care, aiming at finding a diagnosis, understanding aetiology and improving treatment and outcome. The psychological impact of genetic counselling from patients' or parents' perspectives is, however, unknown. We studied the counselee-reported outcome of genetic counselling before and after genetic testing for epilepsy by evaluating empowerment - a key outcome goal of counselling reflecting cognitive, decisional and behavioural control, emotional regulation and hope - and anxiety. We asked patients or their parents (for those16 years or intellectually disabled) referred for genetic testing for epilepsy in two university hospitals between June 2014 and 2017 to complete the same two questionnaires at three timepoints: before and after pre-test counselling and after post-test counselling. Empowerment was measured with the Genetic Counselling Outcome Scale (GCOS-18); anxiety with the short State Trait Anxiety Inventory (STAI-6). A total of 63 participants (55 parents with the age of 29-66 years; 8 patients with the age of 21-42 years) were included in our study. Empowerment significantly increased during the genetic counselling trajectory with a medium effect size (p 0.001, d = 0.57). A small but significant increase in empowerment was already seen after pre-test counselling (p = 0.038, d = 0.29). Anxiety did not change significantly during the counselling trajectory (p = 0.223, d = -0.24). Our study highlights that patients with epilepsy or their parents show a clinically relevant increase in empowerment after genetic counselling. Empowerment was already increased after pre-test counselling, suggesting the importance of counselling before initiating genetic testing for epilepsy. However, individual differences in changes in empowerment and anxiety were seen, suggesting that counselling could be further improved, based on individual needs.

Contains fulltext : 243999.pdf (Publisher’s version ) (Open Access) The kinesin family member 5A (KIF5A) motor domain variants are typically associated with hereditary spastic paraplegia (HSP) or Charcot-Marie-Tooth 2 (CMT2), while KIF5A tail variants predispose to amyotrophic lateral sclerosis (ALS) and neonatal intractable myoclonus. Variants within the stalk domain of KIF5A are relatively rare. We describe a family of three patients with a complex HSP phenotype and a likely pathogenic KIF5A stalk variant. More family members were reported to have walking difficulties. When reviewing the literature on KIF5A stalk variants, we found 22 other cases. The phenotypes varied with most cases having (complex) HSP/CMT2 or ALS. Symptom onset varied from childhood to adulthood and common additional symptoms for HSP are involvement of the upper limbs, sensorimotor polyneuropathy, and foot deformities. We conclude that KIF5A variants lead to a broad clinical spectrum of disease. Phenotype distribution according to variants in specific domains occurs often in the motor and tail domain but are not definite. However, variants in the stalk domain are not bound to a specific phenotype.

Objectives We ascertained the prevalence of ictal arrhythmias to explain the high rate of sudden unexpected death in epilepsy (SUDEP) in Dravet syndrome (DS). Methods We selected cases with clinical DS, ≥6 years, SCN1A mutation, and ≥1 seizure/week. Home‐based ECG recordings were performed for 20 days continuously. Cases were matched for age and sex to two epilepsy controls with no DS and ≥1 major motor seizure during video‐EEG. We determined the prevalence of peri‐ictal asystole, bradycardia, QTc changes, and effects of convulsive seizures (CS) on heart rate, heart rate variability (HRV), and PR/QRS. Generalized estimating equations were used to account for multiple seizures within subjects, seizure type, and sleep/wakefulness. Results We included 59 cases. Ictal recordings were obtained in 45 cases and compared to 90 controls. We analyzed 547 seizures in DS (300 CS) and 169 in controls (120 CS). No asystole occurred. Postictal bradycardia was more common in controls (n = 11, 6.5%) than cases (n = 4, 0.7%; P = 0.002). Peri‐ictal QTc‐lengthening (≥60ms) occurred more frequently in DS (n = 64, 12%) than controls (n = 8, 4.7%, P = 0.048); pathologically prolonged QTc was rare (once in each group). In DS, interictal HRV was lower compared to controls (RMSSD P = 0.029); peri‐ictal values did not differ between the groups. Prolonged QRS/PR was rare and more common in controls (QRS: one vs. none; PR: three vs. one). Interpretation We did not identify major arrhythmias in DS which can directly explain high SUDEP rates. Peri‐ictal QTc‐lengthening was, however, more common in DS. This may reflect unstable repolarization and an increased propensity for arrhythmias.

Objective Genetic causes are increasingly identified in patients with focal epilepsy. These genetic causes may be related to the effectiveness of epilepsy surgery. We aimed to assess the use and yield of genetic testing in a large cohort of patients who were evaluated for epilepsy surgery. Methods We performed a retrospective single‐center consecutive cohort study of patients who were evaluated for surgery between 1990 and 2016. Within this cohort, we assessed the use of genetic testing—either before or after presurgical decision‐making. We evaluated genetic results as well as the outcome of presurgical decision‐making and surgery, and compared these end points for different subgroups—especially MRI‐positive vs MRI‐negative patients. Patients with tuberous sclerosis (TSC) and KRIT1 mutations were excluded from analysis. Results Of the 2385 epilepsy patients who were evaluated for surgery, 1280 (54%) received surgical treatment in our center. Of the entire cohort, 325 (14%) underwent genetic testing, comprising 156 of 450 MRI‐negative patients (35%) vs 169 of 1935 MRI‐positive patients (9%). A genetic cause of epilepsy was found in 40 of the 325 patients (12%, 2% of the entire cohort), mainly consisting of mutations in ion channel function and synaptic transmission genes, and mTOR pathway gene mutations. Three of the seven patients with mTOR pathway gene mutations underwent surgery; two achieved complete seizure freedom. One of the 17 patients with germline mutations in ion channel function and synaptic transmission genes received resective surgery but was not rendered seizure‐free; two other patients underwent invasive intracranial EEG‐monitoring before being rejected. Significance This study shows that genetic testing is increasingly applied in focal epilepsy patients who are considered for epilepsy surgery. The diagnostic yield of genetic testing is highest in next generation sequencing techniques, and the outcome of genetic testing assists selecting eligible patients for invasive intracranial monitoring and resective surgery.

Background and ObjectivesPurine-rich element-binding protein A (PURA) gene encodes Pur-α, a conserved protein essential for normal postnatal brain development. Recently, a PURA syndrome characterized by intellectual disability, hypotonia, epilepsy, and dysmorphic features was suggested. The aim of this study was to define and expand the phenotypic spectrum of PURA syndrome by collecting data, including EEG, from a large cohort of affected patients.MethodsData on unpublished and published cases were collected through the PURA Syndrome Foundation and the literature. Data on clinical, genetic, neuroimaging, and neurophysiologic features were obtained.ResultsA cohort of 142 patients was included. Characteristics of the PURA syndrome included neonatal hypotonia, feeding difficulties, and respiratory distress. Sixty percent of the patients developed epilepsy with myoclonic, generalized tonic-clonic, focal seizures, and/or epileptic spasms. EEG showed generalized, multifocal, or focal epileptic abnormalities. Lennox-Gastaut was the most common epilepsy syndrome. Drug refractoriness was common: 33.3% achieved seizure freedom. We found 97 pathogenic variants in PURA without any clear genotype-phenotype associations.DiscussionThe PURA syndrome presents with a developmental and epileptic encephalopathy with characteristics recognizable from neonatal age, which should prompt genetic screening. Sixty percent have drug-resistant epilepsy with focal or generalized seizures. We collected more than 90 pathogenic variants without observing overt genotype-phenotype associations.

Objective: To detect determinants for photoparoxysmal EEG response (PPR) in SCN1A -related Dravet syndrome (DS). Methods: Data were studied from nationwide medical histories and EEGs of DS-patients ( n =53; 31 males, age 2–19years). Detailed questionnaires on visual stimuli were completed by parents ( n =49). Results: PPR was found in 22 patients (42%; median age 1.25yr), and repeatedly in 17%. PPR (17% of 249 intermittent photic stimulation (IPS)-EEGs) occurred more often with optimal IPS protocols (OR 2.11 [95%CI 1.09–4.13]) and in EEGs showing spontaneous epileptiform abnormalities (OR 5.08 [95%CI 2.05–12.55]). PPR-positive patients tended to be younger at first ( p =0.072) and second seizure ( p =0.049), showed severe intellectual disability ( p =0.042), and had more often spontaneous occipital epileptiform abnormalities ( p Clinical sensitivity was reported in medical files in 22% of patients and by parents in 43% (self-induction 24%). Clinical or EEG proven visual sensitivity was detected in 65% of cases. Conclusions: Sensitivity to visual stimuli is very common in DS and more often noticed by parents than confirmed by EEG. Detection of PPR improves with repetitive tests using accurate IPS protocols. Significance: Photosensitivity is an important feature in DS and seems to be a marker of the severity of the disorder. Therefore repeated standardized IPS should be encouraged.

Objective:To examine the role of mutations in GABRB3 encoding the β3 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 from multiplex families. The phenotypic spectrum of the mutation carriers ranged from simple febrile seizures, genetic epilepsies with febrile seizures plus, and epilepsy with myoclonic-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 β3, together with α5 and γ2s 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.

Contains fulltext : 208476.pdf (Publisher’s version ) (Open Access)

ObjectiveTo evaluate the effect of chenodeoxycholic acid treatment on disease progression in cerebrotendinous xanthomatosis (CTX).MethodsIn this retrospective cohort study, we report the clinical long-term follow-up characteristics of 56 Dutch patients with CTX. Age at diagnosis was correlated with clinical characteristics and with the course of modified Rankin Scale (mRS) and Expanded Disability Status Scale (EDSS) scores at follow-up.ResultsMedian follow-up time was 8 years (6 months–31.5 years). Patients diagnosed and treated before the age of 24 years had a significantly better outcome at follow-up. When considering only patients with a good treatment adherence (n = 43), neurologic symptoms, if present, disappeared in all patients who were diagnosed before the age of 24 and treated since. Furthermore, treatment prevented the development of new neurologic symptoms during follow-up. In contrast, 61% of the patients diagnosed and treated after the age of 24 showed deterioration of the neurologic symptoms, with parkinsonism as a treatment-resistant feature. There was an improvement or stabilization in favor of patients diagnosed and treated before the age of 24 compared to those treated after the age of 24: 100% vs 58% for mRS scores and 100% vs 50% for EDSS scores, respectively.ConclusionsTreatment start at an early age can reverse and even prevent the development of neurologic symptoms in CTX. This study emphasizes the importance of early diagnosis in CTX and provides a rationale to include CTX in newborn screening programs.

ObjectiveThe study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in QARS encephalopathy.MethodsThrough diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic QARS variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding.ResultsBiallelic pathogenic variants in QARS cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype.ConclusionsThese data revealed first genotype-phenotype associations and may serve for improved interpretation of new QARS variants and well-founded genetic counseling.

International audience; Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels control neuronal excitability and their dysfunction has been linked to epileptogenesis but few individuals with neurological disorders related to variants altering HCN channels have been reported so far. In 2014, we described five individuals with epileptic encephalopathy due to de novo HCN1 variants. To delineate HCN1-related disorders and investigate genotype-phenotype correlations further, we assembled a cohort of 33 unpublished patients with novel pathogenic or likely pathogenic variants: 19 probands carrying 14 different de novo mutations and four families with dominantly inherited variants segregating with epilepsy in 14 individuals, but not penetrant in six additional individuals. Sporadic patients had epilepsy with median onset at age 7 months and in 36% the first seizure occurred during a febrile illness. Overall, considering familial and sporadic patients, the predominant phenotypes were mild, including genetic generalized epilepsies and genetic epilepsy with febrile seizures plus (GEFS+) spectrum. About 20% manifested neonatal/infantile onset otherwise unclassified epileptic encephalopathy. The study also included eight patients with variants of unknown significance: one adopted patient had two HCN1 variants, four probands had intellectual disability without seizures, and three individuals had missense variants inherited from an asymptomatic parent. Of the 18 novel pathogenic missense variants identified, 12 were associated with severe phenotypes and clustered within or close to transmembrane domains, while variants segregating with milder phenotypes were located outside transmembrane domains, in the intracellular N- and C-terminal parts of the channel. Five recurrent variants were associated with similar phenotypes. Using whole-cell patch-clamp, we showed that the impact of 12 selected variants ranged from complete loss-of-function to significant shifts in activation kinetics and/or voltage dependence. Functional analysis of three different substitutions altering Gly391 revealed that these variants had different consequences on channel biophysical properties. The Gly391Asp variant, associated with the most severe, neonatal phenotype, also had the most severe impact on channel function. Molecular dynamics simulation on channel structure showed that homotetramers were not conducting ions because the permeation path was blocked by cation(s) strongly complexed to the Asp residue, whereas heterotetramers showed an instantaneous current component possibly linked to deformation of the channel pore. In conclusion, our results considerably expand the clinical spectrum related to HCN1 variants to include common generalized epilepsy phenotypes and further illustrate how HCN1 has a pivotal function in brain development and control of neuronal excitability.

ObjectivePathogenic variants in SCN1A can give rise to extremely variable disease severities that may be indistinguishable at their first presentation. We aim to find clinical features that can help predict the evolution of seizures into Dravet syndrome and clinical features that predict cognitive outcome in Dravet syndrome. We specifically investigate the role of contraindicated medication (CIM) as a possible modifier of cognitive decline.MethodsA cohort of 164 Dutch participants with SCN1A-related seizures was evaluated. Clinical data were collected from medical records and semistructured telephone interviews. Cognitive function was classified by a child neurologist, neuropsychologist, and clinical geneticist. Several clinical variables, including duration of CIM use in the first 5years of disease, were evaluated in univariate and multivariate analyses.ResultsA longer duration of CIM use in the first 5years after seizure onset was significantly associated with a worse cognitive outcome at time of inclusion, and with lower interpolated intelligence quotient/developmental quotient scores after the first 5years of disease in Dravet syndrome patients. CIM use remained a significant predictor for cognitive outcome in a multivariate regression model, as did age at the first observation of developmental delay and age at first afebrile seizure. Age at first afebrile seizure was the most accurate predictor for evolution of seizures into Dravet syndrome for the complete cohort.SignificanceOur data suggest that a longer CIM use in the first 5years of disease can have negative effects on cognitive outcome in Dravet syndrome. An early diagnosis is essential to avoid these drugs. Furthermore, we identified age at first afebrile seizure as an important predictor for evolution of seizures into Dravet syndrome and for the severity of Dravet syndrome, which can be used to counsel parents of young patients with SCN1A-related seizures.

Aims. In recent years, many different DNA mutations underlying the development of refractory epilepsy have been discovered. However, genetic diagnostics are still not routinely performed during presurgical evaluation and reports on epilepsy surgery outcome for patients with genetic refractory epilepsy are limited. We aimed to create an overview of the literature on seizure outcome following epilepsy surgery in patients with different genetic causes of refractory epilepsy. Methods. We systematically searched PubMed and Embase prior to January 2017 and included studies describing treatment outcome following epilepsy surgery in patients with genetic causes of epilepsy. We excluded studies in which patients were described with epilepsy due to Tuberous Sclerosis Complex or Sturge-Weber syndrome (since this extensive body of research has recently been described elsewhere) and articles in which surgery was aimed to be palliative. Results. We identified 24 eligible articles, comprising a total of 82 patients who had undergone surgery for (mainly childhood-onset) refractory epilepsy due to 15 different underlying genetic causes. The success rate of surgery varied widely across these different genetic causes. Surgery was almost never effective in patients with epilepsy due to mutations in genes involved in channel function and synaptic transmission, whereas surgery was significantly more successful regarding seizure control in patients with epilepsy due to mutations in the mTOR pathway. Patients with a lesion on MRI tended to have higher seizure freedom rates than those who were MRI-negative. Conclusion. Although the evidence is still scarce, this systematic review suggests that studying genetic variations in patients with refractory epilepsy could help guide the selection of surgical candidates.

Objective: Phenotypes caused by de novo SCN1A pathogenic variants are very variable, ranging from severely affected patients with Dravet syndrome to much milder genetic epilepsy febrile seizures plus cases. The most important determinant of disease severity is the type of variant, with variants that cause a complete loss of function of the SCN1A protein (α-subunit of the neuronal sodium channel Nav1.1) being detected almost exclusively in Dravet syndrome patients. However, even within Dravet syndrome disease severity ranges greatly, and consequently other disease modifiers must exist. A better prediction of disease severity is very much needed in daily practice to improve counseling, stressing the importance of identifying modifying factors in this patient group. We evaluated 128 participants with de novo, pathogenic SCN1A variants to investigate whether mosaicism, caused by postzygotic mutation, is a major modifier in SCN1A-related epilepsy. Methods: Mosaicism was investigated by reanalysis of the pathogenic SCN1A variants using single molecule molecular inversion probes and next generation sequencing with high coverage. Allelic ratios of pathogenic variants were used to determine whether mosaicism was likely. Selected mosaic variants were confirmed by droplet digital polymerase chain reaction and sequencing of different tissues. Developmental outcome was classified based on available data on intelligence quotient and school functioning/education. Results: Mosaicism was present for 7.5% of de novo pathogenic SCN1A variants in symptomatic patients. Mosaic participants were less severely affected than nonmosaic participants if only participants with truncating variants are considered (distribution of developmental outcome scores, Mann-Whitney U, P =.023). Significance: Postzygotic mutation is a common phenomenon in SCN1A-related epilepsies. Participants with mosaicism have on average milder phenotypes, suggesting that mosaicism can be a major modifier of SCN1A-related diseases. Detection of mosaicism has important implications for genetic counseling and can be achieved by deep sequencing of unique reads.

NBEA is a candidate gene for autism, and de novo variants have been reported in neurodevelopmental disease (NDD) cohorts. However, NBEA has not been rigorously evaluated as a disease gene, and associated phenotypes have not been delineated. We identified 24 de novo NBEA variants in patients with NDD, establishing NBEA as an NDD gene. Most patients had epilepsy with onset in the first few years of life, often characterized by generalized seizure types, including myoclonic and atonic seizures. Our data show a broader phenotypic spectrum than previously described, including a myoclonic-astatic epilepsy-like phenotype in a subset of patients. Ann Neurol 2018;84:796-803

Mutations in SCN8A are associated with epilepsy and intellectual disability. SCN8A encodes for sodium channel Nav1.6, which is located in the brain. Gain-of-function missense mutations in SCN8A are thought to lead to increased firing of excitatory neurons containing Nav1.6, and therefore to lead to increased seizure susceptibility. We hypothesized that sodium channel blockers could have a beneficial effect in patients with SCN8A-related epilepsy by blocking the overactive Nav1.6 and thereby counteracting the effect of the mutation. Herein, we describe 4 patients with a missense SCN8A mutation and epilepsy who all show a remarkably good response on high doses of phenytoin and loss of seizure control when phenytoin medication was reduced, while side effects were relatively mild. In 2 patients, repeated withdrawal of phenytoin led to the reoccurrence of seizures. Based on the findings in these patients and the underlying molecular mechanism we consider treatment with (high-dose) phenytoin as a possible treatment option in patients with difficult-to-control seizures due to an SCN8A mutation. Electronic supplementary material The online version of this article (doi:10.1007/s13311-015-0372-8) contains supplementary material, which is available to authorized users.

Objective:To study the effect of vaccination-associated seizure onset on disease course and estimate the risk of subsequent seizures after infant pertussis combination and measles, mumps, and rubella (MMR) vaccinations in Dravet syndrome (DS).Methods:We retrospectively analyzed data from hospital medical files, child health clinics, and the vaccination register for children with DS and pathogenic SCN1A mutations. Seizures within 24 hours after infant whole-cell, acellular, or nonpertussis combination vaccination or within 5 to 12 days after MMR vaccination were defined as "vaccination-associated." Risks of vaccination-associated seizures for the different vaccines were analyzed in univariable and in multivariable logistic regression for pertussis combination vaccines and by a self-controlled case series analysis using parental seizure registries for MMR vaccines. Disease courses of children with and without vaccination-associated seizure onset were compared.Results:Children who had DS (n = 77) with and without vaccination-associated seizure onset (21% and 79%, respectively) differed in age at first seizure (median 3.7 vs 6.1 months, p Conclusions:Our results suggest that vaccination-associated earlier seizure onset does not alter disease course in DS, while the risk of subsequent vaccination-associated seizures is probably vaccine-specific.

Introduction: Early-onset epileptic encephalopathy caused by biallelic SLC13A5 mutations is characterized by seizure onset in the first days of life, refractory epilepsy and develop mental delay. Little detailed information about the brain MRI features is available in these patients.Methods: Observational study describing the neuro-imaging findings in eight patients (five families) with mutations in the SLC13A5 gene. Seven infants had an MRI in the neonatal period, two had a follow-up MRI at the age of 6 and 18 months and one only at 13 months. One patient had follow-up MRIs at 11 and 16 months and 3 and 6 years of age, but no neonatal MRI.Results: All patients presented with refractory neonatal seizures on the first day of life after an uncomplicated pregnancy and term delivery. Six out of seven infants with a neonatal MRI had a characteristic MRI pattern, with punctate white matter lesions (PWML), which were no longer visible at the age of 6 months, but led to gliotic scarring visible on MRI at the age of 18 months. The same pattern of gliotic scarring was seen on the MRIs of the infant without a neonatal scan. One infant had signal abnormalities in the white matter suspected of PWML on T2WI, but these could not be confirmed on other sequences.Conclusion: In infants presenting with therapy resistant seizures in the first days after birth, without a clear history of hypoxic-ischemic encephalopathy, but with PWML on their neonatal MRI, a diagnosis of SCL13A5 related epileptic encephalopathy should be considered. (C) 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

International audience; Mutations in SCN2A, a gene encoding the voltage-gated sodium channel Nav1.2, have been associated with a spectrum of epilepsies and neurodevelopmental disorders. Here, we report the phenotypes of 71 patients and review 130 previously reported patients. We found that (i) encephalopathies with infantile/childhood onset epilepsies (≥3 months of age) occur almost as often as those with an early infantile onset (

Summary Objective Recently, de novo SCN8A missense mutations have been identified as a rare dominant cause of epileptic encephalopathies (EIEE13). Functional studies on the first described case demonstrated gain-of-function effects of the mutation. We describe a novel de novo mutation of SCN8A in a patient with epileptic encephalopathy, and functional characterization of the mutant protein. Design Whole exome sequencing was used to discover the variant. We generated a mutant cDNA, transfected HEK293 cells, and performed Western blotting to assess protein stability. To study channel functional properties, patch-clamp experiments were carried out in transfected neuronal ND7/23 cells. Results The proband exhibited seizure onset at 6 months of age, diffuse brain atrophy, and more profound developmental impairment than the original case. The mutation p.Arg233Gly in the voltage sensing transmembrane segment D1S4 was present in the proband and absent in both parents. This mutation results in a temperature-sensitive reduction in protein expression as well as reduced sodium current amplitude and density and a relative increased response to a slow ramp stimulus, though this did not result in an absolute increased current at physiological temperatures. Conclusion The new de novo SCN8A mutation is clearly deleterious, resulting in an unstable protein with reduced channel activity. This differs from the gain-of-function attributes of the first SCN8A mutation in epileptic encephalopathy, pointing to heterogeneity of mechanisms. Since Nav1.6 is expressed in both excitatory and inhibitory neurons, a differential effect of a loss-of-function of Nav1.6 Arg223Gly on inhibitory interneurons may underlie the epilepsy phenotype in this patient.

Background Punctate white matter lesions (PWMLs) are small focal patches of increased signal intensity (SI) on T1- and decreased SI on T2-weighted magnetic resonance imaging (MRI). To date, there have been few reports of PWMLs in term born infants. Objective To identify associated diagnoses and factors predictive of clinical outcome in (near) term infants with PWMLs. Methods MRI studies and clinical records of (near) term infants, with PWMLs on MRI scans performed in two institutions in the first 28 postnatal days were reviewed. The PWMLs were classified according to their number, pattern and distribution. The medical records were examined to assess the associated diagnoses and determine the neurodevelopmental outcome at >12 months of age. Infants with congenital heart defect(s), those who had neonatal surgery, or those with perinatal arterial ischemic stroke were not eligible for the study. Results Forty-two (near) term infants with PWMLs were included. The major clinical association was perinatal asphyxia, present in 19/42 (45%). Ten (24%) had a history of seizures unrelated to asphyxia or a genetic diagnosis. Eleven (26%) had pathological genetic mutations. Other diagnoses, without seizures were identified in 2 (5%). The lesion load of PWMLs was high (>6) in 30/42 (71%). Evidence of irreversible white matter injury was present in 5 infants who had follow-up MRI performed between 18 and 24 months of age, because of clinical concerns. Five infants died and 37 had follow-up at a median age of 24 months. Neurodevelopmental outcome was poorest amongst 6 infants (16%) whose PWMLs occurred in the setting of a genetic disorder. Conclusion PWMLs in (near) term infants represent white matter injury that may evolve into gliosis and/or white matter loss. Infants with PWMLs in the setting of a genetic disorder appeared at most risk of a poor outcome.

Purpose: Differentiating between Dravet syndrome and non-Dravet SCN1A-related phenotypes is important for prognosis regarding epilepsy severity, cognitive development, and comorbidities. When a child is diagnosed with genetic epilepsy with febrile seizures plus (GEFS+) or febrile seizures (FS), accurate prognostic information is essential as well, but detailed information on seizure course, seizure freedom, medication use, and comorbidities is lacking for this milder patient group. In this cross-sectional study, we explore disease characteristics in milder SCNTA-related phenotypes and the nature, occurrence, and relationships of SCN1A-related comorbidities in both patients with Dravet and non-Dravet syndromes.Methods: A cohort of 164 Dutch participants with SCN1A-related seizures was evaluated, consisting of 116 patients with Dravet syndrome and 48 patients with either GEFS+, febrile seizures plus (FS+), or FS. Clinical data were collected from medical records, semi-structured telephone interviews, and three questionnaires: the Functional Mobility Scale (FMS), the Pediatric Quality of Life Inventory (PedsQL) Measurement Model, and the Child or Adult Behavior Checklists (CBCL/ABCL).Results: Walking disabilities and severe behavioral problems affect 71% and 43% of patients with Dravet syndrome respectively and are almost never present in patients with non-Dravet syndromes. These comorbidities are strongly correlated to lower quality-of-life (QoL) scores. Less severe comorbidities occur in patients with non-Dravet syndromes: learning problems and psychological/behavioral problems are reported for 27% and 38% respectively. The average QoL score of the non-Dravet group was comparable with that of the general population. The majority of patients with non-Dravet syndromes becomes seizure-free after 10 years of age (85%).Conclusions: Severe behavioral problems and walking disabilities are common in patients with Dravet syndrome and should receive specific attention during clinical management. Although the epilepsy course of patients with non-Dravet syndromes is much more favorable, milder comorbidities frequently occur in this group as well. Our results may be of great value for clinical care and informing newly diagnosed patient and their parents about prognosis. (C) 2018 The Authors. Published by Elsevier Inc.

Background: A disruption of the extracellular matrix (ECM) of the intracranial arterial wall is a likely contributing factor in the pathogenesis of intracranial aneurysms. If this is a generalized process, patients with subarachnoid haemorrhage (SAH) may have subtle signs of a general laxity of the connective tissue. We performed a pilot study to assess general laxity in SAH patients and to examine which tests for joint mobility can be best used in these patients. Methods: In 59 SAH patients and sex- and age-matched controls we compared: (1) joint mobility (scores of Beighton and Bulbena and the total range of joint motion); (2) skin extensibility, and (3) bone quantity and stiffness. For the analyses we used the independent-samples T test and linear regression with adjustment for possible confounders. Results: The patients had a higher degree of joint mobility according to the Beighton criteria (total score of 4 in patients vs. 2 in controls, p = 0.001) and the summation of Z scores of active range of motion measurements (0.1 in patients vs. –0.1 in controls, p = 0.0036), and a tendency towards a higher degree of joint mobility according to the Bulbena criteria (total score of 3 in patients vs. 2 in controls, p = 0.097) and the summation of active range of joint motion measurements (1,292 in patients vs. 1,275 in controls, p = 0.13). No differences were found for the other investigated characteristics. Conclusions: Our preliminary results suggest that SAH patients have a higher degree of joint mobility than controls. The Beighton score can be best used in our patient population.

Background: Relatively high rates of complications occur after operation for unruptured intracranial aneurysms. Published data on endovascular treatment suggest lower rates of complications. We measured the impact of treatment of unruptured aneurysms by clipping or coiling on functional health, quality of life, and the level of anxiety and depression. Methods: In three centres, we prospectively collected data on patients with an unruptured aneurysm who were treated by clipping or coiling. Treatment assignment was left to the discretion of the treating physicians. Before, 3 and 12 months after treatment, we used standardised questionnaires to assess functional health (Rankin Scale score), quality of life (SF-36, EuroQol), and the level of anxiety and depression (Hospital Anxiety and Depression Scale). Results: Nineteen patients were treated by coiling and 32 by clipping. In the surgical group, 4 patients (12%) had a permanent complication; 36 of all 37 aneurysms (97%) were successfully clipped. Three months after operation, quality of life was worse than before operation; 12 months after operation, it had improved but had not completely returned to baseline levels. Scores for depression were higher than in the general population. In the endovascular group, no complications with permanent deficits occurred; 16 of 19 aneurysms (84%) were occluded by more than 90%. One patient died from rupture of the previously coiled aneurysm. In the others, quality of life after 3 months and after 1 year was similar to that before treatment. Conclusions: In the short term, operation of patients with an unruptured aneurysm has a considerable impact on functional health and quality of life. After 1 year, recovery occurs but it is incomplete. Coil embolisation does not affect functional health and quality of life.

Background and Purpose — The objective of this study was to assess the health-related quality of life and symptoms of anxiety and depression in patients who are aware of the presence of a patent aneurysm or arteriovenous malformation. Methods — Participants were retrospectively identified and invited to participate in the study; consenting participants were interviewed in a face-to-face setting by means of 2 questionnaires assessing health-related quality of life (Sickness Impact Profile [SIP] and the MOS Short Form-36 [SF-36]) and psychological state (Hospital Anxiety and Depression Scale [HADS]). We used Student’s t test statistics to compare the scores of the study population with the scores of reference populations. Results — We identified 21 patients, of whom 9 had an aneurysm and 12 had an arteriovenous malformation. Compared with the reference population, these patients had a reduced quality of life for sleep and rest (difference of SIP means, 6.8; 95% CI, 3.1 to 10.5), emotional behavior (10.1; 95% CI, 5.7 to 14.6), mobility (5.4; 95% CI, 2.1 to 8.7), social interactions (5.3; 95% CI, 1.6 to 8.9), and alertness behavior (11.9; 95% CI, 6.2 to 17.5). The SIP psychosocial subscore (7.1; 95% CI, 3.9 to 10.2) and total SIP score (4.7; 95% CI, 2.2 to 7.2) were also significantly impaired. For the SF-36 domains, social functioning was significantly decreased compared with the reference population (8.9; 95% CI, 0.1 to 17.7). HADS scores for depression were similar for patients and the reference population. Conclusions — Our study shows that knowledge of harboring an unoccluded untreated intracranial aneurysm or arteriovenous malformation reduces quality of life, most prominently on the psychosocial domains, without leading to substantially raised levels of anxiety and depression.

BACKGROUND Neurosurgical clipping used to be the standard method of occluding intracranial aneurysms, but controlled detachable coils are increasingly used to obliterate aneurysms by endosaccular packing. REVIEW SUMMARY A systematic review of observational studies on embolization with coils showed in patients with a ruptured aneurysm a complete occlusion in 52% of aneurysms, independence at follow-up in 89% of patients, and a procedure related mortality of 1.1%. There is no consensus with regard to the indications for surgical or endovascular treatment. A recently published randomized trial on early coiling versus early operation did not show any differences in clinical outcome after 3 and 12 months, but the small number of patients included precludes firm conclusions. Comparisons between endovascular and surgical treatment should not only address safety and clinical outcome, but also the long-term angiographic results and the risk of recurrent hemorrhage after treatment. In current practice, many patients with a basilar bifurcation aneurysm are treated by embolization with coils. In many patients with a middle cerebral artery aneurysm operation is the preferred treatment. For all other aneurysm locations preference for coiling or clipping depends on the clinical condition of the patient, the configuration of the aneurysm, and on the experience and skills of the local endovascular and neurosurgical team. CONCLUSIONS Endovascular treatment of intracranial aneurysms has gained widespread acceptance. Preference for coiling or clipping depends on patient and aneurysm characteristics, and on the local expertise.

Background and Purpose — Balloon occlusion of the parent vessel and endosaccular coiling are both frequently used for treatment of intracavernous aneurysms of the carotid artery. We performed a systematic review of studies reporting on these two treatment modalities to assess the rate of complications, rate of successful aneurysm occlusion, and clinical condition after treatment. Methods — We performed a medline search for studies published between January 1974 and May 1999 and hand-searched recent volumes of 21 journals. Two authors independently extracted data by means of a standardized data extraction form. Results — We found 35 studies reporting on 316 patients. Only 9 of the 35 studies reported on more than 5 patients; in only 9 studies (totaling 85 patients), well-defined outcome measures were used. Twenty-five studies (with 78% of all patients included in the review) reported on balloon occlusion. Complications during or in the first 24 hours after the balloon occlusion occurred in 4 of 247 patients (1.6%; 95% CI, 0.01% to 3.2%) and late ischemic complications in 5 of 148 patients (3.4%; 95% CI, 0.43% to 6.4%). Clinical follow-up was performed in 21 of 25 studies on treatment by means of balloon occlusion (148 [60%] of the 247 patients). None of the 68 patients treated by embolization with coils had a complication (0%; 95% CI, 0% to 4.3%). Of 157 aneurysms treated by balloon occlusion, 153 were completely thrombosed (97.5%; 95% CI, 95% to 100%). After coiling, 52 of 65 aneurysms (80%; 95% CI, 70% to 90%) were occluded by >90%. Conclusions — Many studies included in this review had methodological weaknesses. The available data suggest that both balloon occlusion and endosaccular coiling are reasonably safe and result in occlusion of the aneurysm in the majority of patients. However, long-term outcomes have not yet been reported.

Importance: Knowing the range of symptoms seen in patients with a missense or loss-of-function variant in KCNB1 and how these symptoms correlate with the type of variant will help clinicians with diagnosis and prognosis when treating new patients.Objectives: To investigate the clinical spectrum associated with KCNB1 variants and the genotype-phenotype correlations.Design, Setting, and Participants: This study summarized the clinical and genetic information of patients with a presumed pathogenic variant in KCNB1. Patients were identified in research projects or during clinical testing. Information on patients from previously published articles was collected and authors contacted if feasible. All patients were seen at a clinic at one of the participating institutes because of presumed genetic disorder. They were tested in a clinical setting or included in a research project.Main Outcomes and Measures: The genetic variant and its inheritance and information on the patient's symptoms and characteristics in a predefined format. All variants were identified with massive parallel sequencing and confirmed with Sanger sequencing in the patient. Absence of the variant in the parents could be confirmed with Sanger sequencing in all families except one.Results: Of 26 patients (10 female, 15 male, 1 unknown; mean age at inclusion, 9.8 years; age range, 2-32 years) with developmental delay, 20 (77%) carried a missense variant in the ion channel domain of KCNB1, with a concentration of variants in region S5 to S6. Three variants that led to premature stops were located in the C-terminal and 3 in the ion channel domain. Twenty-one of 25 patients (84%) had seizures, with 9 patients (36%) starting with epileptic spasms between 3 and 18 months of age. All patients had developmental delay, with 17 (65%) experiencing severe developmental delay; 14 (82%) with severe delay had behavioral problems. The developmental delay was milder in 4 of 6 patients with stop variants and in a patient with a variant in the S2 transmembrane element rather than the S4 to S6 region.Conclusions and Relevance: De novo KCNB1 missense variants in the ion channel domain and loss-of-function variants in this domain and the C-terminal likely cause neurodevelopmental disorders with or without seizures. Patients with presumed pathogenic variants in KCNB1 have a variable phenotype. However, the type and position of the variants in the protein are (imperfectly) correlated with the severity of the disorder.

Most patients with Dravet syndrome have de novo mutations in the neuronal voltage-gated sodium channel type 1 (SCN1A) gene. We report on two unrelated fathers with severe childhood epilepsy compatible with a possible diagnosis of Dravet syndrome, who both have a child with Dravet syndrome. Analysis of the SCN1A gene revealed a pathogenic mutation in both children. One father exhibited somatic mosaicism for the mutation detected in his son. A relatively favorable cognitive outcome in patients with Dravet syndrome patients may be explained by somatic mosaicism for the SCN1A mutation in brain tissue. A mild form of Dravet syndrome in adult patients is associated with a high recurrence risk and possibly a more severe epilepsy phenotype in their offspring.

We describe the clinical presentation, radiological and clinical results in six consecutive patients with a giant vertebrobasilar aneurysm treated by bilateral vertebral artery balloon occlusion. Five patients presented with headache and signs of brain-stem compression and one with subarachnoid haemorrhage. In all patients vertebral artery balloon occlusion was performed. In four, this followed successful test occlusion. In one patient, who did not tolerate the test occlusion, a bypass from the external carotid to the posterior cerebral artery preceded definitive vertebral artery occlusion. One patient underwent bypass surgery prior to test occlusion. At 6-22 months follow-up three patients had a good functional outcome and showed unchanged size or shrinkage of the aneurysm on MRI. Three other patients died; one from recurrent haemorrhage, and two probably from delayed brain-stem ischaemia. The presence of two large posterior communicating arteries predicted good functional outcome, which was also related to the clinical condition at presentation, and the degree of brain-stem compression and oedema on MRI. Bilateral vertebral artery balloon occlusion can be considered in patients with otherwise untreatable giant vertebrobasilar aneurysms. If test occlusion is not tolerated, a surgical bypass to the posterior circulation can be considered.

Article abstract— Objective: To assess the time course of secondary ischemia and first rebleeding and the relation between the timing of operation and the time course of secondary ischemia in a consecutive series of patients with aneurysmal subarachnoid hemorrhage (SAH). Methods: Life table methods were used to assess the daily rates of ischemia and of rebleeding on day 0, day 1 to 3, day 4 to 10, day 11 to 14, and day 15 to 21. The authors compared the time course of secondary ischemia between patients operated within 4 days of SAH and those operated after 10 days. Results: Of 346 patients included, 220 were operated, 131 within 4 days and 74 after 10 days. The rebleed rate was highest on the day of the initial hemorrhage, then diminished, and increased slightly again during the second week. The rate of secondary ischemia was highest on day 4, diminished after day 10, but peaked again from day 14 to 18 for patients who were operated later than 10 days after aneurysmal rupture. The peak rate of ischemia was much higher after early than after late operation. Although patients with early operation were in a better clinical condition on admission, with a relatively low risk of secondary ischemia, the overall rate of secondary ischemia was as high as in patients with delayed operation. From day 11 to 21 the rebleed rate was higher than the rate of secondary ischemia. Conclusions: These results indicate that operation is a risk factor for ischemia, especially when performed early. If operation is postponed, it should be planned soon after day 10, because of the relatively high rebleed rate from day 11 to 21.

Autosomal dominant lateral temporal lobe epilepsy (ADLTE) is characterized by focal seizures with auditory features or aphasia. Mutations in the leucine-rich glioma-inactivated 1 (LGI1) gene have been reported in up to 50% of families with ADLTE. Attention-deficit/hyperactivity disorder (ADHD) symptoms have not yet been reported in these families. Clinical data were collected from a family with five affected members. Leucine-rich glioma-inactivated 1 exons and boundaries were sequenced by standard methods. Attention-deficit/hyperactivity disorder symptoms were scored based on the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria. Affected members had seizures with auditory features and psychic auras, and some experienced nightmares. A heterozygous c.431+1G>A substitution in LGI1 was detected in all members. Significantly more hyperactivity symptoms were found in family members carrying the LGI1 mutation. This study expands the phenotypic spectrum associated with ADLTE due to LGI1 mutation and underlines the need for more systematic evaluation of ADHD and related symptoms.

Objective: To describe the phenotypes and penetrance of paroxysmal kinesigenic dyskinesia (PKD), a movement disorder characterized by attacks of involuntary movements occurring after sudden movements, infantile convulsion and choreoathetosis (ICCA) syndrome, and benign familial infantile convulsions (BFIC), caused by PRRT2 mutations.Methods: We performed clinical and genetic studies in 3 large families with ICCA, 2 smaller families with PKD, and 4 individuals with sporadic PKD. Migraine was also present in several individuals.Results: We detected 3 different PRRT2 heterozygous mutations: the recurrent p.Arg217Profs*8 mutation, previously reported, was identified in 2 families with ICCA, 2 families with PKD, and one individual with sporadic PKD; one novel missense mutation (p.Ser275Phe) was detected in the remaining family with ICCA; and one novel truncating mutation (p.Arg217*) was found in one individual with sporadic PKD. In the 2 remaining individuals with sporadic PKD, PRRT2 mutations were not detected. Importantly, PRRT2 mutations did not cosegregate with febrile convulsions or with migraine. The estimated penetrance of PRRT2 mutations was 61%, if only the PKD phenotype was considered; however, if infantile convulsions were also taken into account, the penetrance was nearly complete. Considering our findings and those reported in literature, 23 PRRT2 mutations explain similar to 56% of the families analyzed.Conclusions: PRRT2 mutations are the major cause of PKD or ICCA, but they do not seem to be involved in the etiology of febrile convulsions and migraine. The identification of PRRT2 as a major gene for the PKD-ICCA-BFIC spectrum allows better disease classification, molecular confirmation of the clinical diagnosis, and genetic testing and counseling. Neurology (R) 2012;79:777-784

Dorothee G.A. Kasteleijn-Nolst Trenite *, Linda Volkers , Eric Strengman , Herman M. Schippers , Willem Perquin , Gerrit-Jan de Haan , Anastasia O. Gkountidi , Ruben van’t Slot , Stan F. van de Graaf , Bosanka Jocic-Jakubi , Giuseppe Capovilla , Athanasios Covanis , Pasquale Parisi , Pierangelo Veggiotti , Mario Brinciotti , Gemma Incorpora , Marta Piccioli , Laura Cantonetti , Samuel F. Berkovic , Ingrid E. Scheffer , Eva H. Brilstra , Anja C.M. Sonsma , Adri J. Bader , Carolien G.F. de Kovel , Bobby P.C. Koeleman a

Electrical status epilepticus in sleep syndrome is the association of the electroencephalographic pattern and deficits in language or global cognitive function and behavioral problems. The etiology is often unknown, but genetic risk factors have been implicated. Array-based comparative genomic hybridization was used to identify copy number variations in 13 children with electrical status epilepticus in sleep syndrome to identify possible underlying risk factors. Seven copy number variations were detected in 4 of the 13 patients, which consisted of 6 novel gains and 1 loss, the recurrent 15q13.3 microdeletion. Two patients carried a probable pathogenic copy number variation containing a gene involved in the cholinergic pathway. Genetic aberrations in patients with electrical status epilepticus in sleep syndrome can provide an entry in the investigation of the etiology of electrical status epilepticus in sleep. However, further studies are needed to confirm our findings.

Idiopathic generalized epilepsies account for 30% of all epilepsies. Despite a predominant genetic aetiology, the genetic factors predisposing to idiopathic generalized epilepsies remain elusive. Studies of structural genomic variations have revealed a significant excess of recurrent microdeletions at 1q21.1, 15q11.2, 15q13.3, 16p11.2, 16p13.11 and 22q11.2 in various neuropsychiatric disorders including autism, intellectual disability and schizophrenia. Microdeletions at 15q13.3 have recently been shown to constitute a strong genetic risk factor for common idiopathic generalized epilepsy syndromes, implicating that other recurrent microdeletions may also be involved in epileptogenesis. This study aimed to investigate the impact of five microdeletions at the genomic hotspot regions 1q21.1, 15q11.2, 16p11.2, 16p13.11 and 22q11.2 on the genetic risk to common idiopathic generalized epilepsy syndromes. The candidate microdeletions were assessed by high-density single nucleotide polymorphism arrays in 1234 patients with idiopathic generalized epilepsy from North-western Europe and 3022 controls from the German population. Microdeletions were validated by quantitative polymerase chain reaction and their breakpoints refined by array comparative genomic hybridization. In total, 22 patients with idiopathic generalized epilepsy (1.8%) carried one of the five novel microdeletions compared with nine controls (0.3%) (odds ratio = 6.1; 95% confidence interval 2.8-13.2; chi(2) = 26.7; 1 degree of freedom; P = 2.4 x 10(-7)). Microdeletions were observed at 1q21.1 [Idiopathic generalized epilepsy (IGE)/control: 1/1], 15q11.2 (IGE/control: 12/6), 16p11.2 IGE/control: 1/0, 16p13.11 (IGE/control: 6/2) and 22q11.2 (IGE/control: 2/0). Significant associations with IGEs were found for the microdeletions at 15q11.2 (odds ratio = 4.9; 95% confidence interval 1.8-13.2; P = 4.2 x 10(-4)) and 16p13.11 (odds ratio = 7.4; 95% confidence interval 1.3-74.7; P = 0.009). Including nine patients with idiopathic generalized epilepsy in this cohort with known 15q13.3 microdeletions (IGE/control: 9/0), parental transmission could be examined in 14 families. While 10 microdeletions were inherited (seven maternal and three paternal transmissions), four microdeletions occurred de novo at 15q13.3 (n = 1), 16p13.11 (n = 2) and 22q11.2 (n = 1). Eight of the transmitting parents were clinically unaffected, suggesting that the microdeletion itself is not sufficient to cause the epilepsy phenotype. Although the microdeletions investigated are individually rare (

Periventricular heterotopia (PH) occurs when collections of neurons lay along the lateral ventricles or just beneath. Human Filamin A gene (FLNA) mutations are associated with classical X-linked bilateral periventricular nodular heterotopia (PNH), featuring contiguous heterotopic nodules, mega cisterna magna, cardiovascular malformations and epilepsy. FLNA encodes an F-actin-binding cytoplasmic phosphoprotein and is involved in early brain neurogenesis and neuronal migration. A rare, recessive form of bilateral PNH with microcephaly and severe delay is associated with mutations of the ADP-ribosylation factor guanine nucleotide-exchange factor-2 (ARFGEF2) gene, required for vesicle and membrane trafficking from the trans-Golgi. However, PH is a heterogeneous disorder. We studied clinical and brain MRI of 182 patients with PH and, based on its anatomic distribution and associated birth defects, identified 15 subtypes. Classical bilateral PNH represented the largest group (98 patients: 54%). The 14 additional phenotypes (84 patients: 46%) included PNH with Ehlers-Danlos syndrome (EDS), temporo-occipital PNH with hippocampal malformation and cerebellar hypoplasia, PNH with fronto-perisylvian or temporo-occipital polymicrogyria, posterior PNH with hydrocephalus, PNH with microcephaly, PNH with frontonasal dysplasia, PNH with limb abnormalities, PNH with fragile-X syndrome, PNH with ambiguous genitalia, micronodular PH, unilateral PNH, laminar ribbon-like and linear PH. We performed mutation analysis of FLNA in 120 patients, of whom 72 (60%) had classical bilateral PNH and 48 (40%) other PH phenotypes, and identified 25 mutations in 40 individuals. Sixteen mutations had not been reported previously. Mutations were found in 35 patients with classical bilateral PNH, in three with PNH with EDS and in two with unilateral PNH. Twenty one mutations were nonsense and frame-shift and four missense. The high prevalence of mutations causing protein truncations confirms that loss of function is the major cause of the disorder. FLNA mutations were found in 100% of familial cases with X-linked PNH (10 families: 8 with classical bilateral PNH, 1 with EDS and 1 with unilateral PH) and in 26% of sporadic patients with classical bilateral PNH. Overall, mutations occurred in 49% of individuals with classical bilateral PNH irrespective of their being familial or sporadic. However, the chances of finding a mutation were exceedingly gender biased with 93% of mutations occurring in females and 7% in males. The probability of finding FLNA mutations in other phenotypes was 4% but was limited to the minor variants of PNH with EDS and unilateral PNH. Statistical analysis considering all 42 mutations described so far identifies a hotspot region for PNH in the actin-binding domain (P < 0.05).

Quality of life was measured by means of the sickness impact profile (SIP) questionnaire in a prospectively collected, consecutive series of 25 patients with perimesencephalic haemorrhage. A mean of two years and four months (range six months to six years) after the perimesencephalic haemorrhage, quality of life scores of the (former) patients were comparable with those of a random sample from the Dutch population. For physical aspects the patients showed even less dysfunction than controls. It is concluded that a perimesencephalic haemorrhage does not reduce quality of life or capacity to work.

Background: In patients with acute life threatening diseases, and in their relatives, the ability to make a balanced decision on participation in a clinical trial may be impaired. Objectives: To assess what relevant information could be recalled by patients who were living independently after a subarachnoid haemorrhage, and by their relatives; and to determine how these patients and relatives had reacted to the informed consent encounter. Methods: Twenty months (range 7 to 31) after treatment for subarachnoid haemorrhage, 49 patients and 47 relatives who had participated in one of two randomised trials on medical management were interviewed. The interview consisted of items on: spontaneous recall and knowledge of trial design; understanding of the trial design and the informed consent procedure; the amount and clarity of the information given; and reasons for participating. Finally patients and relatives were asked whether they would participate again in similar circumstances. Results: One third of the patients recalled having participated in a clinical trial. Thirteen per cent of the patients and 20% of the relatives felt that the information supplied had not been sufficient. Nine per cent of the patients and half the relatives had read the written information. None of the patients and one relative thought that participation had been obligatory. Twenty eight per cent of the patients and 94% of the relatives felt in retrospect that they had been capable of making an adequate decision. Virtually all patients and relatives would participate again in similar circumstances. Conclusions: Many patients and their relatives have little recall of the informed consent procedure and the essentials of acute subarachnoid haemorrhage trials. However, most were satisfied with the overall procedure and would participate again.

Background —Embolization with coils is increasingly used for the treatment of intracranial aneurysms. To assess the percentage of complications, the percentage of aneurysm occlusion, and the short-term outcome, we performed a systematic review of studies on embolization with controlled detachable or pushable coils. Summary of Review —To find studies on embolization with coils, we performed a MEDLINE search from January 1990 to March 1997, checked all reference lists of the studies found, performed a Science Citation Index search on Guglielmi , and hand searched recent volumes of 25 journals. Two authors independently extracted data by means of a standardized data extraction form from 48 eligible studies totalling 1383 patients. Permanent complications of embolization with controlled detachable coils occurred in 46 of 1256 patients (3.7%; 95% CI, 2.7% to 4.9%); 400 of 744 aneurysms (54%; 95% CI, 50% to 57%) were completely occluded. By means of weighted linear regression, no relation between baseline characteristics and outcome measurements was found. The results in the prespecified subgroups of patients with a ruptured aneurysm, an unruptured aneurysm, or a basilar bifurcation aneurysm were essentially the same as the overall results. Conclusions —Short-term results indicate that embolization with coils is a reasonably safe treatment for patients with an unruptured aneurysm and for patients with aneurysmal subarachnoid hemorrhage. The effectiveness in terms of complete occlusion of the aneurysm is moderate. Randomized trials are warranted to compare surgical clipping with embolization with coils.

OBJECTIVES Although long term outcome of patients with perimesencephalic haemorrhage, a benign subset of subarachnoid haemorrhage, is excellent, some patients report an episode of amnesia for the first hours to days after the ictus. The relation between the occurrence of amnesia and the size of the ventricles on CT, including the temporal horns, were studied in patients with perimesencephalic haemorrhage. METHODS Twenty seven consecutive patients with perimesencephalic haemorrhage were asked about the occurrence of amnesia. Age adjusted bicaudate indices and third ventricle sizes were calculated. Linear measurements of the temporal horn were taken in three directions: anterior-posterior, medial-lateral, and oblique. Additionally, enlargement of the temporal horns was assessed with the “naked eye”. RESULTS Ten of the 27 patients reported an episode of transient amnesia; in these patients the mean sizes of the temporal horns were larger than in patients without amnesia, ranging from a factor of 1.7 for the medial-lateral measurement to a factor of 2.3 for the anterior-posterior measurement. Most of the patients with amnesia had relative bicaudate indices and relative third ventricle sizes> 1, and all had enlarged temporal horns at “naked eye” assessment. CONCLUSION About one third of patients with perimesencephalic haemorrhage have an episode of amnesia shortly after the bleed. The occurrence of amnesia is associated with enlargement of the temporal horns, and might be explained by temporary hippocampal dysfunction.