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Find video protocols related to scientific articles indexed in Pubmed.
EEG-fMRI in myoclonic astatic epilepsy (Doose syndrome).
Neurology
PUBLISHED: 04-02-2014
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To identify neuronal networks underlying generalized spike and wave discharges (GSW) in myoclonic astatic epilepsy (MAE).
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DEPDC5 mutations in genetic focal epilepsies of childhood.
Ann. Neurol.
PUBLISHED: 02-18-2014
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Recent studies reported DEPDC5 loss-of-function mutations in different focal epilepsy syndromes. Here we identified 1 predicted truncation and 2 missense mutations in 3 children with rolandic epilepsy (3 of 207). In addition, we identified 3 families with unclassified focal childhood epilepsies carrying predicted truncating DEPDC5 mutations (3 of 82). The detected variants were all novel, inherited, and present in all tested affected (n=11) and in 7 unaffected family members, indicating low penetrance. Our findings extend the phenotypic spectrum associated with mutations in DEPDC5 and suggest that rolandic epilepsy, albeit rarely, and other nonlesional childhood epilepsies are among the associated syndromes.
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Mutations in STX1B, encoding a presynaptic protein, cause fever-associated epilepsy syndromes.
Nat. Genet.
PUBLISHED: 02-13-2014
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Febrile seizures affect 2-4% of all children and have a strong genetic component. Recurrent mutations in three main genes (SCN1A, SCN1B and GABRG2) have been identified that cause febrile seizures with or without epilepsy. Here we report the identification of mutations in STX1B, encoding syntaxin-1B, that are associated with both febrile seizures and epilepsy. Whole-exome sequencing in independent large pedigrees identified cosegregating STX1B mutations predicted to cause an early truncation or an in-frame insertion or deletion. Three additional nonsense or missense mutations and a de novo microdeletion encompassing STX1B were then identified in 449 familial or sporadic cases. Video and local field potential analyses of zebrafish larvae with antisense knockdown of stx1b showed seizure-like behavior and epileptiform discharges that were highly sensitive to increased temperature. Wild-type human syntaxin-1B but not a mutated protein rescued the effects of stx1b knockdown in zebrafish. Our results thus implicate STX1B and the presynaptic release machinery in fever-associated epilepsy syndromes.
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Atypical Vitamin B6 Deficiency: A Rare Cause of Unexplained Neonatal and Infantile Epilepsies.
J. Child Neurol.
PUBLISHED: 10-10-2013
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ALDH7A1 and PNPO deficiencies are rare inborn errors of vitamin B6 metabolism causing perinatal seizure disorders. The phenotypic variability, however, is broad. To assess the frequency of these deficiencies in unexplained infantile epilepsy, we screened 113 patients for mutations in both genes. We identified 1 patient with an epilepsy phenotype resembling Dravet syndrome and likely pathogenic mutations in ALDH7A1. Presenting features were highly atypical of pyridoxine-dependent epilepsy, including febrile seizures, response to anticonvulsive drugs, and periods of seizure freedom without pyridoxine treatment. "Hidden" vitamin B6 deficiencies might be rare but treatable causes of unexplained epilepsy extending beyond the classical phenotypes.
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Mutations in GRIN2A cause idiopathic focal epilepsy with rolandic spikes.
Nat. Genet.
PUBLISHED: 07-18-2013
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Idiopathic focal epilepsy (IFE) with rolandic spikes is the most common childhood epilepsy, comprising a phenotypic spectrum from rolandic epilepsy (also benign epilepsy with centrotemporal spikes, BECTS) to atypical benign partial epilepsy (ABPE), Landau-Kleffner syndrome (LKS) and epileptic encephalopathy with continuous spike and waves during slow-wave sleep (CSWS). The genetic basis is largely unknown. We detected new heterozygous mutations in GRIN2A in 27 of 359 affected individuals from 2 independent cohorts with IFE (7.5%; P = 4.83 × 10(-18), Fishers exact test). Mutations occurred significantly more frequently in the more severe phenotypes, with mutation detection rates ranging from 12/245 (4.9%) in individuals with BECTS to 9/51 (17.6%) in individuals with CSWS (P = 0.009, Cochran-Armitage test for trend). In addition, exon-disrupting microdeletions were found in 3 of 286 individuals (1.0%; P = 0.004, Fishers exact test). These results establish alterations of the gene encoding the NMDA receptor NR2A subunit as a major genetic risk factor for IFE.
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Iterative phenotyping of 15q11.2, 15q13.3 and 16p13.11 microdeletion carriers in pediatric epilepsies.
Epilepsy Res.
PUBLISHED: 02-18-2013
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Microdeletions at 15q11.2, 15q13.3 and 16p13.11 are known genetic risk factors for idiopathic generalized epilepsies and other neurodevelopmental disorders. The full phenotypic range of this microdeletion triad in pediatric epilepsies is unknown. We attempted to describe associated phenotypes in a cohort of pediatric epilepsy patients. We screened 570 patients with pediatric epilepsies including idiopathic generalized epilepsies, focal epilepsies and fever-associated epilepsy syndromes for microdeletions at 15q11.2, 15q13.3 and 16p13.11 using quantitative polymerase chain reaction. Identified microdeletions were confirmed using array comparative hybridization. Ten microdeletions in 15q11.2 (n=3), 15q13.3 (n=3) and 16p13.11 (n=4) were identified (1.8%). 9/10 microdeletions were identified in patients with IGE (6/101, 6.0%) or patients with generalized EEG patterns without seizures (3/122, 2.5%). 6/10 microdeletion carriers had various degrees of ID; the frequency of microdeletions in patients with epilepsy and ID was higher (4.6%) compared to patients with normal intellect (0.9%). Iterative phenotyping revealed a wide range of generalized epilepsy phenotypes. In our pediatric cohort, recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 are mainly associated with phenotypes related to idiopathic generalized epilepsies or related EEG patterns. In contrast to previous reports, these recurrent microdeletions are virtually absent in focal epilepsies, FS, FS+ and GEFS+. Microdeletion carriers have a five-fold risk to present with various degrees of ID compared to patients without these risk factors. This microdeletion triad might help delineate a novel spectrum of epilepsy phenotypes classifiable through clinical, electrographic and genetic data.
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Structural genomic variation in childhood epilepsies with complex phenotypes.
Eur. J. Hum. Genet.
PUBLISHED: 01-27-2013
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A genetic contribution to a broad range of epilepsies has been postulated, and particularly copy number variations (CNVs) have emerged as significant genetic risk factors. However, the role of CNVs in patients with epilepsies with complex phenotypes is not known. Therefore, we investigated the role of CNVs in patients with unclassified epilepsies and complex phenotypes. A total of 222 patients from three European countries, including patients with structural lesions on magnetic resonance imaging (MRI), dysmorphic features, and multiple congenital anomalies, were clinically evaluated and screened for CNVs. MRI findings including acquired or developmental lesions and patient characteristics were subdivided and analyzed in subgroups. MRI data were available for 88.3% of patients, of whom 41.6% had abnormal MRI findings. Eighty-eight rare CNVs were discovered in 71 out of 222 patients (31.9%). Segregation of all identified variants could be assessed in 42 patients, 11 of which were de novo. The frequency of all structural variants and de novo variants was not statistically different between patients with or without MRI abnormalities or MRI subcategories. Patients with dysmorphic features were more likely to carry a rare CNV. Genome-wide screening methods for rare CNVs may provide clues for the genetic etiology in patients with a broader range of epilepsies than previously anticipated, including in patients with various brain anomalies detectable by MRI. Performing genome-wide screens for rare CNVs can be a valuable contribution to the routine diagnostic workup in patients with a broad range of childhood epilepsies.European Journal of Human Genetics advance online publication, 27 November 2013; doi:10.1038/ejhg.2013.262.
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The role of SLC2A1 in early onset and childhood absence epilepsies.
Epilepsy Res.
PUBLISHED: 01-08-2013
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Early Onset Absence Epilepsy constitutes an Idiopathic Generalized Epilepsy with absences starting before the age of four years. Mutations in SLC2A1, encoding the glucose transporter, account for approximately 10% of EOAE cases. The role of SLC2A1 mutations in absence epilepsies with a later onset has not been assessed. We found two mutation carriers in 26 EOAE patients, while no mutations were found in 124 probands affected by CAE or JAE.
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Variability of EEG-fMRI findings in patients with SCN1A-positive Dravet syndrome.
Epilepsia
PUBLISHED: 01-07-2013
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Dravet syndrome (DS) or severe myoclonic epilepsy of infancy is an intractable epileptic encephalopathy of early childhood that is caused by a mutation in the SCN1A gene in most patients. The aim of this study was to identify a syndrome-specific epileptic network underlying interictal epileptiform discharges (IEDs) in patients with DS.
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Exon-disrupting deletions of NRXN1 in idiopathic generalized epilepsy.
Epilepsia
PUBLISHED: 01-07-2013
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Neurexins are neuronal adhesion molecules located in the presynaptic terminal, where they interact with postsynaptic neuroligins to form a transsynaptic complex required for efficient neurotransmission in the brain. Recently, deletions and point mutations of the neurexin 1 (NRXN1) gene have been associated with a broad spectrum of neuropsychiatric disorders. This study aimed to investigate if NRXN1 deletions also increase the risk of idiopathic generalized epilepsies (IGEs).
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RBFOX1 and RBFOX3 mutations in rolandic epilepsy.
PLoS ONE
PUBLISHED: 01-01-2013
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Partial deletions of the gene encoding the neuronal splicing regulator RBFOX1 have been reported in a range of neurodevelopmental diseases, including idiopathic generalized epilepsy. The RBFOX1 protein and its homologues (RBFOX2 and RBFOX3) regulate alternative splicing of many neuronal transcripts involved in the homeostatic control of neuronal excitability. In this study, we explored if structural microdeletions and exonic sequence variations in RBFOX1, RBFOX2, RBFOX3 confer susceptibility to rolandic epilepsy (RE), a common idiopathic focal childhood epilepsy. By high-density SNP array screening of 289 unrelated RE patients, we identified two hemizygous deletions, a 365?kb deletion affecting two untranslated 5-terminal exons of RBFOX1 and a 43 kb deletion spanning exon 3 of RBFOX3. Exome sequencing of 242 RE patients revealed two novel probably deleterious variants in RBFOX1, a frameshift mutation (p.A233Vfs*74) and a hexanucleotide deletion (p.A299_A300del), and a novel nonsense mutation in RBFOX3 (p.Y287*). Although the three variants were inherited from unaffected parents, they were present in all family members exhibiting the RE trait clinically or electroencephalographically with only one exception. In contrast, no deleterious mutations of RBFOX1 and RBFOX3 were found in the exomes of 6503 non-RE subjects deposited in the Exome Variant Server database. The observed RBFOX3 exon 3 deletion and nonsense mutation suggest that RBFOX3 represents a novel risk factor for RE, indicating that exon deletions and truncating mutations of RBFOX1 and RBFOX3 contribute to the genetic variance of partial and generalized idiopathic epilepsy syndromes.
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Absence seizures with intellectual disability as a phenotype of the 15q13.3 microdeletion syndrome.
Epilepsia
PUBLISHED: 11-02-2011
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15q13.3 microdeletions are the most common genetic findings identified in idiopathic generalized epilepsies to date, and they are present in up to 1% of patients. In addition, 15q13.3 microdeletions have been described in patients with epilepsy as part of a complex neurodevelopmental phenotype. We analyzed a cohort of 570 patients with various pediatric epilepsies for 15q13.3 microdeletions. Screening was performed using quantitative polymerase chain reaction; deletions were confirmed by array comparative genomic hybridization (CGH). We carried out detailed phenotyping of deletion carriers. In total, we identified four pediatric patients with 15q13.3 microdeletions, including one previously described patient. Two of four deletions were de novo, one deletion was inherited from an unaffected parent, and for one patient the inheritance is unknown. All four patients had absence epilepsy with various degrees of intellectual disability. We suggest that absence epilepsy accompanied by intellectual disability may represent a common phenotype of the 15q13.3 microdeletion in pediatric patients with epilepsy.
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Comprehensive analysis of candidate genes for photosensitivity using a complementary bioinformatic and experimental approach.
Epilepsia
PUBLISHED: 08-29-2011
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Photoparoxysmal response (PPR) is a highly heritable electroencephalographic trait characterized by an increased sensitivity to photic stimulation. It may serve as an endophenotype for idiopathic generalized epilepsy. Family linkage studies identified susceptibility loci for PPR on chromosomes 5q35.3, 8q21.13, and 16p13.3. This study aimed to identify key candidate genes within these loci. We used bioinformatics tools for gene prioritization integrating information on biologic function, sequence data, gene expression, and others. The prime candidate gene from this analysis was sequenced in 48 photopositive probands. Presumed functional implications of identified polymorphisms were investigated using bioinformatics methods. The glutamate receptor subunit gene GRIN2A was identified as a prime candidate gene. Sequence analysis revealed various new polymorphisms. None of the identified variants was predicted to be functionally relevant. We objectified the selection of candidate genes for PPR without an a priori hypothesis. Particularly among the various ion channel genes in the linkage regions, GRIN2A was identified as the prime candidate gene. GRIN2A mutations have recently been identified in various epilepsies. Even though our mutation analysis failed to demonstrate direct involvement of GRIN2A in photosensitivity, in silico gene prioritization may provide a useful tool for the identification of candidate genes within large genomic regions.
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Impact of ABCC2 genotype on antiepileptic drug response in Caucasian patients with childhood epilepsy.
Pharmacogenet. Genomics
PUBLISHED: 07-30-2011
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Antiepileptic treatment response has been suggested to be modulated by genetic polymorphisms of drug efflux transporters, in particular ABCB1. Recently, we found a significant association of ABCC2 -24C>T with nonresponse, primarily in the context of generalized epilepsy. Moreover, ABCC2 1249G>A was reported to alter transmembranal carbamazepine transport. Therefore, we aimed to confirm the association of ABCC2 variants with pharmacotherapy-resistance in Caucasians mainly affected by partial epilepsy.
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A retrospective population-based study on seizures related to childhood vaccination.
Epilepsia
PUBLISHED: 06-21-2011
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Cases of severe childhood epilepsies in temporal association with vaccination have great impact on the acceptance of vaccination programs by parents and health care providers. However, little is known about the type and frequency of seizures and epilepsy syndromes following vaccination. This study aims to describe the clinical features of children presenting with seizures after vaccination using a register-based cohort.
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Valproate reduces spontaneous generalized spikes and waves but not photoparoxysmal reactions in patients with idiopathic generalized epilepsies.
Epilepsia
PUBLISHED: 04-11-2011
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Patients with idiopathic generalized epilepsies (IGEs) often present with interictal spike-wave discharges (SWDs) at rest (spontaneous SWDs), during hyperventilation, and in response to photic stimulation (photoparoxysmal response or PPR). Valproic acid (VPA) is a first-line antiepileptic drug for therapy of patients with IGE. Herein we investigated the effect of VPA on all three types of SWDs in children and adolescents with IGE.
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A 2 Mb deletion in 14q13 associated with severe developmental delay and hemophagocytic lymphohistiocytosis.
Eur J Med Genet
PUBLISHED: 01-09-2011
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Interstitial deletions of chromosome 14 have rarely been described. We report on a boy in whom a 2 Mb deletion in 14q13 was discovered by array CGH. The deletion was a de novo event. The boy presented with asymmetrical growth retardation at birth. There was severe developmental delay with muscular hypotonia and focal epilepsy with apneic episodes progressing to serial tonic seizures. At the age of 3 3/12 years he was diagnosed with pneumonia. In the further course he developed symptoms of hemophagocytic lymphohistiocytosis. He died due to organ failure. Herein the clinical findings are compared to patients with cytogenetic visible deletions encompassing the region deleted in the proband and the possible connection with the deleted genes.
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A duplication in 1q21.3 in a family with early onset and childhood absence epilepsy.
Epilepsia
PUBLISHED: 09-24-2010
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Early onset absence epilepsy (EOAE) starting before the age of 4 years constitutes a rare subgroup of the idiopathic generalized epilepsies (IGEs). A strong genetic component in IGE has been suggested by twin and family studies. We describe a boy with absence seizures starting at the age of 9 months whose parents both had childhood absence epilepsy. A 192-kb duplication in 1q21.3 was identified in the proband and his father, encompassing the gene CHRNB2 coding for the ?-2 subunit of the nicotinic acetylcholine receptor and the gene ADAR coding for adenosine deaminase, an enzyme responsible for RNA editing. Both are candidate genes for seizure disorders. The duplication was not identified in 191 independent IGE patients (93 EOAE; 98 classical IGE) or in 1,157 population controls.
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Recurrent 200-kb deletions of 16p11.2 that include the SH2B1 gene are associated with developmental delay and obesity.
Genet. Med.
PUBLISHED: 09-03-2010
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The short arm of chromosome 16 is rich in segmental duplications, predisposing this region of the genome to a number of recurrent rearrangements. Genomic imbalances of an approximately 600-kb region in 16p11.2 (29.5-30.1 Mb) have been associated with autism, intellectual disability, congenital anomalies, and schizophrenia. However, a separate, distal 200-kb region in 16p11.2 (28.7-28.9 Mb) that includes the SH2B1 gene has been recently associated with isolated obesity. The purpose of this study was to better define the phenotype of this recurrent SH2B1-containing microdeletion in a cohort of phenotypically abnormal patients not selected for obesity.
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Absence seizures: individual patterns revealed by EEG-fMRI.
Epilepsia
PUBLISHED: 08-17-2010
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Absences are characterized by an abrupt onset and end of generalized 3-4 Hz spike and wave discharges (GSWs), accompanied by unresponsiveness. Although previous electroencephalography-functional magnetic resonance imaging (EEG-fMRI) studies showed that thalamus, default mode areas, and caudate nuclei are involved in absence seizures, the contribution of these regions throughout the ictal evolution of absences remains unclear. Furthermore, animal models provide evidence that absences are initiated by a cortical focus with a secondary involvement of the thalamus. The aim of this study was to investigate dynamic changes during absences.
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Association study of TRPC4 as a candidate gene for generalized epilepsy with photosensitivity.
Neuromolecular Med.
PUBLISHED: 04-19-2010
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Photoparoxysmal response (PPR) is characterized by abnormal visual sensitivity of the brain to photic stimulation. Frequently associated with idiopathic generalized epilepsies (IGEs), it might be an endophenotype for cortical excitability. Transient receptor potential cation (TRPC) channels are involved in the generation of epileptiform discharges, and TRPC4 constitutes the main TRPC channel in the central nervous system. The present study investigated an association of PPR with sequence variations of the TRPC4 gene. Thirty-five single nucleotide polymorphisms (SNP) within TRPC4 were genotyped in 273 PPR probands and 599 population controls. Association analyses were performed for the broad PPR endophenotype (PPR types I-IV; n = 273), a narrow model of affectedness (PPR types III and IV; n = 214) and PPR associated with IGE (PPR/IGE; n = 106) for each SNP and for corresponding haplotypes. Association was found between the intron 5 SNP rs10507456 and PPR/IGE both for single markers (P = 0.005) and haplotype level (P = 0.01). Three additional SNPs (rs1535775, rs10161932 and rs7338118) within the same haplotype block were associated with PPR/IGE at P < 0.05 (uncorrected) as well as two more markers (rs10507457, rs7329459) located in intron 3. Again, the corresponding haplotype also showed association with PPR/IGE. Results were not significant following correction for multiple comparisons by permutation analysis for single markers and Bonferroni-Holm for haplotypes. No association was found between variants in TRPC4 and other phenotypes. Our results showed a trend toward association of TRPC4 variants and PPR/IGE. Further studies including larger samples of photosensitive probands are required to clarify the relevance of TRPC4 for PPR and IGE.
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Deletions in 16p13 including GRIN2A in patients with intellectual disability, various dysmorphic features, and seizure disorders of the rolandic region.
Epilepsia
PUBLISHED: 04-14-2010
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Seizure disorders of the rolandic region comprise a spectrum of different epilepsy syndromes ranging from benign rolandic epilepsy to more severe seizure disorders including atypical benign partial epilepsy/pseudo-Lennox syndrome,electrical status epilepticus during sleep, and Landau-Kleffner syndrome. Centrotemporal spikes are the unifying electroencephalographic hallmark of these benign focal epilepsies, indicating a pathophysiologic relationship between the various epilepsies arising from the rolandic region. The etiology of these epilepsies is elusive, but a genetic component is assumed given the heritability of the characteristic electrographic trait. Herein we report on three patients with intellectual disability, various dysmorphic features, and epilepsies involving the rolandic region, carrying previously undescribed deletions in 16p13. The only gene located in the critical region shared by all three patients is GRIN2A coding for the alpha-2 subunit of the neuronal N-methyl-D-aspartate(NMDA) receptor.
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Four patients with speech delay, seizures and variable corpus callosum thickness sharing a 0.440 Mb deletion in region 1q44 containing the HNRPU gene.
Eur J Med Genet
PUBLISHED: 04-02-2010
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Structural genome aberrations are frequently associated with highly variable congenital phenotypes involving mental retardation and developmental delay. Although some of these aberrations may result in recognizable phenotypes, a high degree of phenotypic variability often complicates a comprehensive clinical and genetic diagnosis. We describe four patients with overlapping deletions in chromosomal region 1q44, who show developmental delay, in particular of expressive speech, seizures, hypotonia, CNS anomalies, including variable thickness of the abnormal corpus callosum in three of them. High resolution oligonucleotide and SNP array-based segmental aneuploidy profiling showed that these three patients share a 0.440 Mb interstitial deletion, which does not overlap with previously published consensus regions of 1q44 deletions. Two copies of AKT3 and ZNF238, two previously proposed dosage sensitive candidate genes for microcephaly and agenesis of the corpus callosum, were retained in two of our patients. The deletion shared by our patients encompassed the FAM36A, HNRPU, EFCAB2 and KIF26B genes. Since HNRPU is involved in the regulation of embryonic brain development, this represents a novel plausible candidate gene for the combination of developmental delay, speech delay, hypotonia, hypo- or agenesis of the corpus callosum, and seizures in patients with 1q44 deletions. Since only one of the two patients with deletions including the ZNF124 gene showed a vermis hypoplasia, mere hemizygosity for this gene is not sufficient to cause this anomaly. Moreover, to reconcile the variability in the corpus callosum thickness, additional mechanisms, such as unmasking of hemizygous mutations, position effects and possible interactions with other loci need consideration.
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Decomposition of neurological multivariate time series by state space modelling.
Bull. Math. Biol.
PUBLISHED: 03-30-2010
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Decomposition of multivariate time series data into independent source components forms an important part of preprocessing and analysis of time-resolved data in neuroscience. We briefly review the available tools for this purpose, such as Factor Analysis (FA) and Independent Component Analysis (ICA), then we show how linear state space modelling, a methodology from statistical time series analysis, can be employed for the same purpose. State space modelling, a generalization of classical ARMA modelling, is well suited for exploiting the dynamical information encoded in the temporal ordering of time series data, while this information remains inaccessible to FA and most ICA algorithms. As a result, much more detailed decompositions become possible, and both components with sharp power spectrum, such as alpha components, sinusoidal artifacts, or sleep spindles, and with broad power spectrum, such as FMRI scanner artifacts or epileptic spiking components, can be separated, even in the absence of prior information. In addition, three generalizations are discussed, the first relaxing the independence assumption, the second introducing non-stationarity of the covariance of the noise driving the dynamics, and the third allowing for non-Gaussianity of the data through a non-linear observation function. Three application examples are presented, one electrocardigram time series and two electroencephalogram (EEG) time series. The two EEG examples, both from epilepsy patients, demonstrate the separation and removal of various artifacts, including hum noise and FMRI scanner artifacts, and the identification of sleep spindles, epileptic foci, and spiking components. Decompositions obtained by two ICA algorithms are shown for comparison.
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EEG-fMRI study of generalized spike and wave discharges without transitory cognitive impairment.
Epilepsy Behav
PUBLISHED: 02-06-2010
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Generalized spike and wave discharges (GSW) are often accompanied by transitory cognitive impairment (TCI). As a possible neurophysiological correlate of TCI, activation in the thalamus and deactivation in the frontoparietal brain regions associated with GSW were discussed in previous studies which used simultaneous recordings of EEG and functional MRI (EEG-fMRI) in patients with absence epilepsy. We report on a girl having GSW up to 10seconds without any clinical concomitants. The girl underwent an EEG-fMRI investigation with simultaneous behavioral testing (continuous performance task). Although GSW repeatedly occurred during the task, no TCI was observed. EEG-fMRI revealed bilateral deactivation in frontoparietal brain areas and activation in the thalamus in association with GSWs. This study challenges the relation between cognitive impairment during absences and the characteristic pattern of thalamic activation and deactivation in frontoparietal areas associated with GSW.
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Role of GRM4 in idiopathic generalized epilepsies analysed by genetic association and sequence analysis.
Epilepsy Res.
PUBLISHED: 02-02-2010
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GRM4 encoding the group III metabotropic glutamate receptor 4 (mGluR4), is located on the chromosomal segment 6p21.3 where tentative susceptibility loci for Juvenile Myoclonic Epilepsy (JME) and Photoparoxysmal Response (PPR) have been mapped. The present candidate gene study examined if variation in GRM4 confers susceptibility to IGE.
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Genome-wide copy number variation in epilepsy: novel susceptibility loci in idiopathic generalized and focal epilepsies.
PLoS Genet.
PUBLISHED: 01-28-2010
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Epilepsy is one of the most common neurological disorders in humans with a prevalence of 1% and a lifetime incidence of 3%. Several genes have been identified in rare autosomal dominant and severe sporadic forms of epilepsy, but the genetic cause is unknown in the vast majority of cases. Copy number variants (CNVs) are known to play an important role in the genetic etiology of many neurodevelopmental disorders, including intellectual disability (ID), autism, and schizophrenia. Genome-wide studies of copy number variation in epilepsy have not been performed. We have applied whole-genome oligonucleotide array comparative genomic hybridization to a cohort of 517 individuals with various idiopathic, non-lesional epilepsies. We detected one or more rare genic CNVs in 8.9% of affected individuals that are not present in 2,493 controls; five individuals had two rare CNVs. We identified CNVs in genes previously implicated in other neurodevelopmental disorders, including two deletions in AUTS2 and one deletion in CNTNAP2. Therefore, our findings indicate that rare CNVs are likely to contribute to a broad range of generalized and focal epilepsies. In addition, we find that 2.9% of patients carry deletions at 15q11.2, 15q13.3, or 16p13.11, genomic hotspots previously associated with ID, autism, or schizophrenia. In summary, our findings suggest common etiological factors for seemingly diverse diseases such as ID, autism, schizophrenia, and epilepsy.
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Recurrent microdeletions at 15q11.2 and 16p13.11 predispose to idiopathic generalized epilepsies.
Brain
PUBLISHED: 10-20-2009
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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 (<1%) in patients with idiopathic generalized epilepsy, they collectively seem to account for a significant fraction of the genetic variance in common idiopathic generalized epilepsy syndromes. The present results indicate an involvement of microdeletions at 15q11.2 and 16p13.11 in epileptogenesis and strengthen the evidence that recurrent microdeletions at 15q11.2, 15q13.3 and 16p13.11 confer a pleiotropic susceptibility effect to a broad range of neuropsychiatric disorders.
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Dyschromatosis ptychotropica: an unusual pigmentary disorder in a boy with epileptic encephalopathy and progressive atrophy of the central nervous system-a novel entity?
Eur. J. Pediatr.
PUBLISHED: 06-09-2009
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The skin and the central nervous system are tissues of common ectodermal origin and share a close ontogenetic relationship. Genetic diseases primarily affecting both organ systems are regularly encountered in both dermatological and neurological settings. Here, we report on a boy with epileptic encephalopathy, severe intellectual disability, optic atrophy, and progressive cerebellar and supratentorial atrophy, reminiscent of progressive encephalopathy with edema and hypsarrythmia (PEHO) syndrome displaying a previously undescribed dyschromatosis in the form of progressive reticulate and mottled hyper- and hypopigmentation of the neck and the inguinal and axillary regions. We hypothesised that this combination of neurological and cutaneous findings has a common aetiology and represents a novel recognisable entity. Because of the unusual dermatological findings, we suggest the term dyschromatosis ptychotropica. Recognition of further cases may help elucidate the aetiology of this condition and give insight into the pathophysiology of both pigmentation disorders and epileptic encephalopathies.
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Non-response to antiepileptic pharmacotherapy is associated with the ABCC2 -24C>T polymorphism in young and adult patients with epilepsy.
Pharmacogenet. Genomics
PUBLISHED: 05-06-2009
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We aimed to evaluate the association of non-response to antiepileptic pharmacotherapy with the frequency of variant alleles in the drug transporter genes ABCB1 and ABCC2 or in the CYP2C locus in young patients with epilepsy and an independent cohort of adults with drug-refractory epilepsy.
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fMRI activation during spike and wave discharges evoked by photic stimulation.
Neuroimage
PUBLISHED: 04-06-2009
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Photoparoxysmal response (PPR) is an electroencephalographic (EEG) trait characterized by the occurrence of epileptiform discharges in response to visual stimulation. Studying this trait helps to learn about mechanisms of epileptogenicity. While simultaneous recordings of EEG and functional MRI (EEG-fMRI) in patients with spontaneous generalised spike-wave discharges (GSW) have revealed activation of the thalamus and deactivation in frontoparietal areas, EEG-fMRI studies on evoked GSW such as PPR are lacking. In this EEG-fMRI study, 30 subjects with reported generalised PPR underwent intermittent photic stimulation (IPS) in a 3 T MR scanner. PPR was elicited in 6 subjects, four diagnosed with idiopathic generalised epilepsy and two with tension-type headache. Because PPR is preceded by synchronization of cortical gamma oscillations, blood oxygenation level-dependent (BOLD) signal changes were analysed at the onset of the PPR (standard regressor) and 3 s before the onset of PPR (early regressor) in one model. In all subjects, IPS led to a significant activation of the visual cortex. Based on the early regressor, PPR associated activation was found in the parietal cortex adjacent to the intraparietal sulcus in five and in the premotor cortex in all 6 subjects. The standard regressor revealed deactivation in early activated areas in all subjects and thalamic activation in one subject. In contrast to spontaneous GSW, these results suggest that PPR is a cortical phenomenon with an involvement of the parietal and frontal cortices. Pronounced haemodynamic changes seen with the early regressor could mirror gamma activity that is known to precede PPR.
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Mapping brain activity on the verge of a photically induced generalized tonic-clonic seizure.
Epilepsia
PUBLISHED: 03-12-2009
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In a photosensitive patient intermittent photic stimulation (IPS) accidentally provoked a generalized tonic-clonic seizure during simultaneous recordings of electroencephalography (EEG) and functional magnetic resonance imaging (fMRI). Before seizure onset, IPS consistently induced generalized photoparoxysmal responses (PPRs). These PPRs were associated with increases in blood oxygen level dependent (BOLD) signal in the visual cortex, the thalamus, and both superior colliculi, and a decrease in BOLD signal in the frontoparietal areas. The BOLD signal in the visual cortex increased in magnitude during consecutive epochs of IPS associated with PPRs. We propose that repeated IPS led to an excessive amount of neuronal activity in the visual cortex that evoked PPRs and finally exceeded a critical threshold and triggered a generalized seizure.
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Hashimoto encephalopathy in a 15-year-old-girl: EEG findings and follow-up.
Pediatr. Neurol.
PUBLISHED: 01-26-2009
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Hashimoto encephalopathy is characterized by severe neuropsychiatric findings, including psychosis, confusion, seizures, stupor, stroke-like episodes, tremor, and myoclonus. The combination of findings is variable. Hashimoto encephalopathy constitutes an important differential diagnosis in patients with encephalopathy. The triad of encephalopathy, corresponding electroencephalographic slowing, and increased protein content in cerebrospinal fluid should prompt testing of anti-thyroid antibodies in blood and cerebrospinal fluid. Elevated antibody levels support the diagnosis. We describe a 15-year-old girl with a fluctuating course of Hashimoto encephalopathy. Electroencephalograms revealed no specific alterations, but widespread slowing of the background activity occurred during two episodes of fluctuating encephalopathy. Cortical edema was indicated by cranial magnetic resonance imaging during the first episode of encephalopathy, in the context of cerebral seizures. Laboratory findings were in accordance with Hashimoto encephalopathy, which was steroid-responsive.
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15q13.3 microdeletions increase risk of idiopathic generalized epilepsy.
Nat. Genet.
PUBLISHED: 01-11-2009
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We identified 15q13.3 microdeletions encompassing the CHRNA7 gene in 12 of 1,223 individuals with idiopathic generalized epilepsy (IGE), which were not detected in 3,699 controls (joint P = 5.32 x 10(-8)). Most deletion carriers showed common IGE syndromes without other features previously associated with 15q13.3 microdeletions, such as intellectual disability, autism or schizophrenia. Our results indicate that 15q13.3 microdeletions constitute the most prevalent risk factor for common epilepsies identified to date.
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Exome sequencing in a family with restless legs syndrome.
Mov. Disord.
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Restless legs syndrome (RLS) has a high familial aggregation. To date, several loci and genetic risk factors have been identified, but no causative gene mutation has been found.
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Genome-wide association analysis of genetic generalized epilepsies implicates susceptibility loci at 1q43, 2p16.1, 2q22.3 and 17q21.32.
, Michael Steffens, Costin Leu, Ann-Kathrin Ruppert, Federico Zara, Pasquale Striano, Angela Robbiano, Giuseppe Capovilla, Paolo Tinuper, Antonio Gambardella, Amedeo Bianchi, Angela la Neve, Giovanni Crichiutti, Carolien G F de Kovel, Dorothée Kasteleijn-Nolst Trenité, Gerrit-Jan de Haan, Dick Lindhout, Verena Gaus, Bettina Schmitz, Dieter Janz, Yvonne G Weber, Felicitas Becker, Holger Lerche, Bernhard J Steinhoff, Ailing A Kleefuss-Lie, Wolfram S Kunz, Rainer Surges, Christian E Elger, Hiltrud Muhle, Sarah von Spiczak, Philipp Ostertag, Ingo Helbig, Ulrich Stephani, Rikke S Møller, Helle Hjalgrim, Leanne M Dibbens, Susannah Bellows, Karen Oliver, Saul Mullen, Ingrid E Scheffer, Samuel F Berkovic, Kate V Everett, Mark R Gardiner, Carla Marini, Renzo Guerrini, Anna-Elina Lehesjoki, Auli Sirén, Michel Guipponi, Alain Malafosse, Pierre Thomas, Rima Nabbout, Stephanie Baulac, Eric Leguern, Rosa Guerrero, José M Serratosa, Philipp S Reif, Felix Rosenow, Martina Mörzinger, Martha Feucht, Fritz Zimprich, Claudia Kapser, Christoph J Schankin, Arvid Suls, Katrin Smets, Peter De Jonghe, Albena Jordanova, Hande Cağlayan, Zuhal Yapici, Destina A Yalcin, Betul Baykan, Nerses Bebek, Ugur Ozbek, Christian Gieger, Heinz-Erich Wichmann, Tobias Balschun, David Ellinghaus, Andre Franke, Christian Meesters, Tim Becker, Thomas F Wienker, Anne Hempelmann, Herbert Schulz, Franz Rüschendorf, Markus Leber, Steffen M Pauck, Holger Trucks, Mohammad R Toliat, Peter Nürnberg, Giuliano Avanzini, Bobby P C Koeleman, Thomas Sander.
Hum. Mol. Genet.
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Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% and account for 20-30% of all epilepsies. Despite their high heritability of 80%, the genetic factors predisposing to GGEs remain elusive. To identify susceptibility variants shared across common GGE syndromes, we carried out a two-stage genome-wide association study (GWAS) including 3020 patients with GGEs and 3954 controls of European ancestry. To dissect out syndrome-related variants, we also explored two distinct GGE subgroups comprising 1434 patients with genetic absence epilepsies (GAEs) and 1134 patients with juvenile myoclonic epilepsy (JME). Joint Stage-1 and 2 analyses revealed genome-wide significant associations for GGEs at 2p16.1 (rs13026414, P(meta) = 2.5 × 10(-9), OR[T] = 0.81) and 17q21.32 (rs72823592, P(meta) = 9.3 × 10(-9), OR[A] = 0.77). The search for syndrome-related susceptibility alleles identified significant associations for GAEs at 2q22.3 (rs10496964, P(meta) = 9.1 × 10(-9), OR[T] = 0.68) and at 1q43 for JME (rs12059546, P(meta) = 4.1 × 10(-8), OR[G] = 1.42). Suggestive evidence for an association with GGEs was found in the region 2q24.3 (rs11890028, P(meta) = 4.0 × 10(-6)) nearby the SCN1A gene, which is currently the gene with the largest number of known epilepsy-related mutations. The associated regions harbor high-ranking candidate genes: CHRM3 at 1q43, VRK2 at 2p16.1, ZEB2 at 2q22.3, SCN1A at 2q24.3 and PNPO at 17q21.32. Further replication efforts are necessary to elucidate whether these positional candidate genes contribute to the heritability of the common GGE syndromes.
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CDKL5 mutations as a cause of severe epilepsy in infancy: clinical and electroencephalographic long-term course in 4 patients.
J. Child Neurol.
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CDKL5 mutations cause severe epilepsy in infancy with subsequent epileptic encephalopathy. As yet, few studies report on long-term observations in patients with CDKL5-related epileptic encephalopathy. In this study, we describe the evolution of the epilepsy phenotype and the electroencephalographic (EEG) features in 4 patients during a maximum observation period of 22 years. All 4 patients had epilepsy starting with focal seizures in the first 3 months of life, evolving to epileptic spasms between the ages of 2 and 6 years and later on to tonic seizures. In 3 patients, epilepsy was resistant to antiepileptic therapy. Although there was no common EEG pattern in all patients, late hypsarrhythmia until the age of 9 years was observed in 2 patients. CDKL5-related epileptic encephalopathies are a group of refractory seizure disorders starting in early infancy. The phenomenon of late hypsarrhythmia may help define a subgroup of patients with severe and adverse outcomes.
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Genome-wide linkage meta-analysis identifies susceptibility loci at 2q34 and 13q31.3 for genetic generalized epilepsies.
Epilepsia
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Genetic generalized epilepsies (GGEs) have a lifetime prevalence of 0.3% with heritability estimates of 80%. A considerable proportion of families with siblings affected by GGEs presumably display an oligogenic inheritance. The present genome-wide linkage meta-analysis aimed to map: (1) susceptibility loci shared by a broad spectrum of GGEs, and (2) seizure type-related genetic factors preferentially predisposing to either typical absence or myoclonic seizures, respectively.
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