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Find video protocols related to scientific articles indexed in Pubmed.
Cortical involvement in focal epilepsies with epileptic spasms.
Epilepsy Res.
PUBLISHED: 04-29-2014
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The pathophysiological mechanisms of epileptic spasms are still poorly understood. The role of subcortical structures has been suggested on the basis of non-localized EEG features and from experimental data. The description of asymmetric spasms associated with lateralized EEG patterns has challenged this view and raises the possibility of a cortical origin. This study investigated the cortical organization of partial seizures associated with epileptic spasms in children undergoing intracerebral EEG recordings for presurgical evaluation. Eleven children with drug resistant epileptic spasms and for whom depth electrode recordings were performed were retrospectively studied. In all children several features suggested a focal origin. Cortical involvement was studied using the "Epileptogenicity Index" (EI). A focal origin was finally demonstrated in 10/11 patients. Seven patients demonstrated pre-ictal changes in the seizure onset zone area. EI analysis showed maximal values in the temporal (n=5), parietal (n=1) or frontal (n=5) cortices. EEG changes were also observed in the premotor cortex during spasms in patients with frontal or parietal seizures and in 3/5 patients with temporal lobe seizures. Good surgical outcome (class I or II) was obtained in 7/10 patients. Seizures associated with epileptic spasms may originate from various cortical regions. Premotor/motor cortices are probably involved in determining ictal clinical changes.
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Mutations in SLC13A5 cause autosomal-recessive epileptic encephalopathy with seizure onset in the first days of life.
Am. J. Hum. Genet.
PUBLISHED: 04-09-2014
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Epileptic encephalopathy (EE) refers to a clinically and genetically heterogeneous group of severe disorders characterized by seizures, abnormal interictal electro-encephalogram, psychomotor delay, and/or cognitive deterioration. We ascertained two multiplex families (including one consanguineous family) consistent with an autosomal-recessive inheritance pattern of EE. All seven affected individuals developed subclinical seizures as early as the first day of life, severe epileptic disease, and profound developmental delay with no facial dysmorphism. Given the similarity in clinical presentation in the two families, we hypothesized that the observed phenotype was due to mutations in the same gene, and we performed exome sequencing in three affected individuals. Analysis of rare variants in genes consistent with an autosomal-recessive mode of inheritance led to identification of mutations in SLC13A5, which encodes the cytoplasmic sodium-dependent citrate carrier, notably expressed in neurons. Disease association was confirmed by cosegregation analysis in additional family members. Screening of 68 additional unrelated individuals with early-onset epileptic encephalopathy for SLC13A5 mutations led to identification of one additional subject with compound heterozygous mutations of SLC13A5 and a similar clinical presentation as the index subjects. Mutations affected key residues for sodium binding, which is critical for citrate transport. These findings underline the value of careful clinical characterization for genetic investigations in highly heterogeneous conditions such as EE and further highlight the role of citrate metabolism in epilepsy.
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Intragenic rearrangements in X-linked intellectual deficiency: results of a-CGH in a series of 54 patients and identification of TRPC5 and KLHL15 as potential XLID genes.
Am. J. Med. Genet. A
PUBLISHED: 04-03-2014
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High-resolution array comparative genomic hybridization (a-CGH) enables the detection of intragenic rearrangements, such as single exon deletion or duplication. This approach can lead to the identification of new disease genes. We report on the analysis of 54 male patients presenting with intellectual deficiency (ID) and a family history suggesting X-linked (XL) inheritance or maternal skewed X-chromosome inactivation (XCI), using a home-made X-chromosome-specific microarray covering the whole human X-chromosome at high resolution. The majority of patients had whole genome array-CGH prior to the selection and we did not include large rearrangements such as MECP2 and FMR1 duplications. We identified four rearrangements considered as causative or potentially pathogenic, corresponding to a detection rate of 8%. Two CNVs affected known XLID genes and were therefore considered as causative (IL1RAPL1 and OPHN1 intragenic deletions). Two new CNVs were considered as potentially pathogenic as they affected interesting candidates for ID. The first CNV is a deletion of the first exon of the TRPC5 gene, encoding a cation channel implicated in dendrite growth and patterning, in a child presenting with ID and an autism spectrum disorder (ASD). The second CNV is a partial deletion of KLHL15, in a patient with severe ID, epilepsy, and anomalies of cortical development. In both cases, in spite of strong arguments for clinical relevance, we were not able at this stage to confirm pathogenicity of the mutations, and the causality of the variants identified in XLID remains to be confirmed.
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Cognitive and adaptive evaluation of 21 consecutive patients with Dravet syndrome.
Epilepsy Behav
PUBLISHED: 01-08-2014
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In order to assess the cognitive and adaptive profiles of school-aged patients with Dravet syndrome (DS), we proposed to evaluate the intelligence and adaptive scores in twenty-one 6- to 10-year-old patients with DS followed in our institution between 1997 and 2013. Fourteen patients were tested using the Wechsler Intelligence Scale for Children (WISC) and the Vineland Adaptive Behavioral Scales (VABS); 6 patients could not be tested with the WISC and were tested with the VABS only, and one was tested with the WISC only. Data regarding the epilepsy were retrospectively collected. Statistical analysis (Spearman rank order and Pearson correlation coefficient) was used to correlate early epilepsy characteristics with the cognitive and adaptive scores. Sodium channel, neuronal alpha-subunit type 1 (SCN1A) was mutated in 19 out of 21 patients. After the age of 6years, none of the DS patients had a normal intelligence quotient (IQ) using WISC (age at the testing period: mean=100±5; median=105months; mean total IQ=47±3; n=15). Only five patients had a verbal and/or a non verbal IQ of more than 60 (points). Their cognitive profile was characterized by an attention deficit, an inability to inhibit impulsive responses, perseverative responses and deficit in planning function. Administering the Vineland Adaptive Behavioral Scales in the same period, we showed that socialization skills were significantly higher than communication and autonomy skills (age at the testing period: mean=100±4; median=100months; n=20). We did not find any significant correlation between the IQ or developmental quotient assessed between 6 and 10years of age and the quantitative and qualitative parameters of epilepsy during the first two years of life in this small group of patients. Despite an overall moderate cognitive deficit in this group of patients, the Vineland Adaptive Behavioral Scales described an adaptive/behavioral profile with low communication and autonomy capacities, whereas the socialization skills were more preserved. This profile was different from the one usually found in young patients with autism and may require specific interventions.
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Early epileptic encephalopathies associated with STXBP1 mutations: Could we better delineate the phenotype?
Eur J Med Genet
PUBLISHED: 10-22-2013
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STXBP1 (MUNC18.1), encoding syntaxin binding protein 1, is a gene causing epileptic encephalopathy. Mutations in STXBP1 have first been reported in early onset epileptic encephalopathy with suppression-bursts, then in infantile spasms and, more recently, in patients with non syndromic mental retardation without epilepsy. We analyzed clinical evolution and brain magnetic resonance imaging in 7 patients (6 females, 1 male) with early onset epileptic encephalopathies associated with STXBP1 mutations. We documented a peculiar brain MRI aspect characterized by frontal hypoplasia and a thin and dysmorphic corpus callosum. The course of the epilepsy was relatively benign. These clinical and neuroradiological features could orient the clinician in selecting patients candidate to genetic testing for STXBP1 gene.
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Diagnosis and outcome of SCN4A-related severe neonatal episodic laryngospasm (SNEL): 2 new cases.
Pediatrics
PUBLISHED: 08-19-2013
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Mutations of SCN4A encoding the skeletal muscle sodium channel Nav 1.4 cause several types of disease, including sodium channel myotonias. The latter may be responsible for neonatal symptoms, including severe neonatal episodic laryngospasm (SNEL). Establishing the diagnosis of SCN4A-related SNEL early in the neonatal period is crucial because treatment is available that can reduce laryngospasm and improve vital and cerebral outcome. We report 2 new unrelated French patients who presented with SNEL. The first patient was initially diagnosed with laryngomalacia and underwent laryngeal surgery in the neonatal period before being diagnosed with myotonia at 14 months of age. The episodes of laryngospasm disappeared spontaneously, although occasional circumstances such as cold exposure could trigger laryngeal reactions; in addition, he developed myotonia corresponding to an adult myotonia permanens phenotype. This patient is now 24 years old and leading a normal life. The second patient was initially diagnosed with gastroesophageal reflux, then SNEL; his condition improved with carbamazepine treatment, and he is now 6 months old. The diagnostic sequence in both patients was the same: first, severe episodic apneic attacks necessitating hospitalization occurring in the first week of life; second, observation of muscle hypertrophy and peripheral hypertonia with a clear myotonic pattern on electromyogram (at 14 and 3 months of age, respectively); third, genetic testing revealing de novo SCN4A G1306E mutation. Both patients have had good therapeutic response to sodium channel blockers (carbamazepine or mexiletine).
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Brain maturation and epilepsy.
Handb Clin Neurol
PUBLISHED: 04-30-2013
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At full term, both glutamate and gamma-amino-butyric acid (GABA) are excitatory; cortical synapses are beginning to appear, there is little myelin in the cerebral hemispheres, and long tracts hardly start to develop. Neonatal myoclonic encephalopathy can result from premature activation of N-methyl-D-aspartate (NMDA) transmission. Benign neonatal seizures and migrating partial seizures in infancy could involve excessive or premature excitability of deep cortical layers. Benign rolandic epilepsy and continuous spike waves in slow sleep are consistent with an excess of both excitatory and inhibitory cortical synapses. West and Lennox-Gastaut syndromes express age-related diffuse cortical hyperexcitability, the pattern depending on the age of occurrence; synchronization of spikes is becoming possible with maturation of the myelin. Idiopathic generalized epilepsy is itself modulated by maturation that causes frontal hyperexcitability generating myoclonic-astatic seizures, between the ages of infantile and juvenile myoclonic epilepsies. Physiological delay of hippocampo-neocortical pathways maturation could account for the delayed occurrence of mesial temporal epilepsy following infantile damage, whereas premature maturation could contribute to fronto-temporal damage characteristic of fever-induced epileptic encephalopathy in school-age children, a dramatic school-age epileptic encephalopathy.
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Similar early characteristics but variable neurological outcome of patients with a de novo mutation of KCNQ2.
Orphanet J Rare Dis
PUBLISHED: 03-08-2013
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Early onset epileptic encephalopathies (EOEEs) are dramatic heterogeneous conditions in which aetiology, seizures and/or interictal EEG have a negative impact on neurological development. Several genes have been associated with EOEE and a molecular diagnosis workup is challenging since similar phenotypes are associated with mutations in different genes and since mutations in one given gene can be associated with very different phenotypes. Recently, de novo mutations in KCNQ2, have been found in about 10% of EOEE patients. Our objective was to confirm that KCNQ2 was an important gene to include in the diagnosis workup of EOEEs and to fully describe the clinical and EEG features of mutated patients.
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Novel compound heterozygous mutations in TBC1D24 cause familial malignant migrating partial seizures of infancy.
Hum. Mutat.
PUBLISHED: 03-07-2013
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Early-onset epileptic encephalopathies (EOEEs) are a group of rare devastating epileptic syndromes of infancy characterized by severe drug-resistant seizures and electroencephalographic abnormalities. The current study aims to determine the genetic etiology of a familial form of EOEE fulfilling the diagnosis criteria for malignant migrating partial seizures of infancy (MMPSI). We identified two inherited novel mutations in TBC1D24 in two affected siblings. Mutations severely impaired TBC1D24 expression and function, which is critical for maturation of neuronal circuits. The screening of TBC1D24 in an additional set of eight MMPSI patients was negative. TBC1D24 loss of function has been associated to idiopathic infantile myoclonic epilepsy, as well as to drug-resistant early-onset epilepsy with intellectual disability. Here, we describe a familial form of MMPSI due to mutation in TBC1D24, revealing a devastating epileptic phenotype associated with TBC1D24 dysfunction.
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Mosaic 15q13.3 deletion including CHRNA7 gene in monozygotic twins.
Eur J Med Genet
PUBLISHED: 02-07-2013
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Deletions in 15q13.3 belong to the most frequently identified recurrent CNVs, and lead to mental retardation, seizures and minor dysmorphism. We report on two monozygotic twin boys with a mosaic 1.5 Mb deletion in 15q13.3, including CHRNA7. The growth parameters were in the normal range for both twins. Both had language delay with hyperactivity, temper tantrums and poor social interaction but attended regular school. The percentage of abnormal cells was 40% on lymphocytes, and 25 and 35% on buccal smear in the first and second twins, respectively. The mosaicism for the 15q13.3 deletion can explain the milder phenotype observed in these two boys.
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Auditory stimuli mimicking ambient sounds drive temporal "delta-brushes" in premature infants.
PLoS ONE
PUBLISHED: 01-01-2013
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In the premature infant, somatosensory and visual stimuli trigger an immature electroencephalographic (EEG) pattern, "delta-brushes," in the corresponding sensory cortical areas. Whether auditory stimuli evoke delta-brushes in the premature auditory cortex has not been reported. Here, responses to auditory stimuli were studied in 46 premature infants without neurologic risk aged 31 to 38 postmenstrual weeks (PMW) during routine EEG recording. Stimuli consisted of either low-volume technogenic "clicks" near the background noise level of the neonatal care unit, or a human voice at conversational sound level. Stimuli were administrated pseudo-randomly during quiet and active sleep. In another protocol, the cortical response to a composite stimulus ("click" and voice) was manually triggered during EEG hypoactive periods of quiet sleep. Cortical responses were analyzed by event detection, power frequency analysis and stimulus locked averaging. Before 34 PMW, both voice and "click" stimuli evoked cortical responses with similar frequency-power topographic characteristics, namely a temporal negative slow-wave and rapid oscillations similar to spontaneous delta-brushes. Responses to composite stimuli also showed a maximal frequency-power increase in temporal areas before 35 PMW. From 34 PMW the topography of responses in quiet sleep was different for "click" and voice stimuli: responses to "clicks" became diffuse but responses to voice remained limited to temporal areas. After the age of 35 PMW auditory evoked delta-brushes progressively disappeared and were replaced by a low amplitude response in the same location. Our data show that auditory stimuli mimicking ambient sounds efficiently evoke delta-brushes in temporal areas in the premature infant before 35 PMW. Along with findings in other sensory modalities (visual and somatosensory), these findings suggest that sensory driven delta-brushes represent a ubiquitous feature of the human sensory cortex during fetal stages and provide a potential test of functional cortical maturation during fetal development.
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Epileptic and nonepileptic features in patients with early onset epileptic encephalopathy and STXBP1 mutations.
Epilepsia
PUBLISHED: 07-19-2011
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STXBP1 (MUNC18-1) mutations have been associated with various types of epilepsies, mostly beginning early in life. To refine the phenotype associated with STXBP1 aberrations in early onset epileptic syndromes, we studied this gene in a cohort of patients with early onset epileptic encephalopathy.
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Depolarizing actions of GABA in immature neurons depend neither on ketone bodies nor on pyruvate.
J. Neurosci.
PUBLISHED: 01-07-2011
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GABA depolarizes immature neurons because of a high [Cl(-)](i) and orchestrates giant depolarizing potential (GDP) generation. Zilberter and coworkers (Rheims et al., 2009; Holmgren et al., 2010) showed recently that the ketone body metabolite DL-3-hydroxybutyrate (DL-BHB) (4 mM), lactate (4 mM), or pyruvate (5 mM) shifted GABA actions to hyperpolarizing, suggesting that the depolarizing effects of GABA are attributable to inadequate energy supply when glucose is the sole energy source. We now report that, in rat pups (postnatal days 4-7), plasma D-BHB, lactate, and pyruvate levels are 0.9, 1.5, and 0.12 mM, respectively. Then, we show that DL-BHB (4 mM) and pyruvate (200 ?M) do not affect (i) the driving force for GABA(A) receptor-mediated currents (DF(GABA)) in cell-attached single-channel recordings, (2) the resting membrane potential and reversal potential of synaptic GABA(A) receptor-mediated responses in perforated patch recordings, (3) the action potentials triggered by focal GABA applications, or (4) the GDPs determined with electrophysiological recordings and dynamic two-photon calcium imaging. Only very high nonphysiological concentrations of pyruvate (5 mM) reduced DF(GABA) and blocked GDPs. Therefore, DL-BHB does not alter GABA signals even at the high concentrations used by Zilberter and colleagues, whereas pyruvate requires exceedingly high nonphysiological concentrations to exert an effect. There is no need to alter conventional glucose enriched artificial CSF to investigate GABA signals in the developing brain.
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New onset refractory convulsive status epilepticus associated with serum neuropil auto-antibodies in a school aged child.
Brain Dev.
PUBLISHED: 08-27-2010
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We report a case of a child that suffered from a severe new onset status epilepticus a few days after a common viral infection. Despite extensive screening, no bacterial, viral or fungal infection could be found. Using immunohistochemical analysis, we found neuronal auto-antibodies directed against the neuropil, in blood and CSF, associated with CSF oligoclonal banding. Status epilepticus was highly refractory to antiepileptic drugs, but improved few days after Intra-Venous Immunoglobulin Injection (IVIG). The patient developed ongoing temporal lobe epilepsy that was still associated with neuropil auto-antibodies. Therefore, screening for antineuronal antibodies should be helpful to characterize and maybe to handle new onset status epilepticus without any obvious aetiology. Further studies should establish the link between epilepsy and such auto-antibodies.
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Novel mutations in EPM2A and NHLRC1 widen the spectrum of Lafora disease.
Epilepsia
PUBLISHED: 08-05-2010
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Lafora disease (LD) is an autosomal recessive form of progressive myoclonus epilepsy with onset in childhood or adolescence and with fatal outcome caused by mutations in two genes: EPM2A and NHLRC1. The aim of this study was to characterize the mutation spectrum in a cohort of unrelated patients with presumed LD.
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A conserved switch in sensory processing prepares developing neocortex for vision.
Neuron
PUBLISHED: 07-02-2010
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Developing cortex generates endogenous activity that modulates the formation of functional units, but how this activity is altered to support mature function is poorly understood. Using recordings from the visual cortex of preterm human infants and neonatal rats, we report a "bursting" period of visual responsiveness during which the weak retinal output is amplified by endogenous network oscillations, enabling a primitive form of vision. This period ends shortly before delivery in humans and eye opening in rodents with an abrupt switch to the mature visual response. The switch is causally linked to the emergence of an activated state of continuous cortical activity dependent on the ascending neuromodulatory systems involved in arousal. This switch is sensory system specific but experience independent and also involves maturation of retinal processing. Thus, the early development of visual processing is governed by a conserved, intrinsic program that switches thalamocortical response properties in anticipation of patterned vision.
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Mutations in GRIN2A and GRIN2B encoding regulatory subunits of NMDA receptors cause variable neurodevelopmental phenotypes.
Nat. Genet.
PUBLISHED: 04-01-2010
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N-methyl-D-aspartate (NMDA) receptors mediate excitatory neurotransmission in the mammalian brain. Two glycine-binding NR1 subunits and two glutamate-binding NR2 subunits each form highly Ca²(+)-permeable cation channels which are blocked by extracellular Mg²(+) in a voltage-dependent manner. Either GRIN2B or GRIN2A, encoding the NMDA receptor subunits NR2B and NR2A, was found to be disrupted by chromosome translocation breakpoints in individuals with mental retardation and/or epilepsy. Sequencing of GRIN2B in 468 individuals with mental retardation revealed four de novo mutations: a frameshift, a missense and two splice-site mutations. In another cohort of 127 individuals with idiopathic epilepsy and/or mental retardation, we discovered a GRIN2A nonsense mutation in a three-generation family. In a girl with early-onset epileptic encephalopathy, we identified the de novo GRIN2A mutation c.1845C>A predicting the amino acid substitution p.N615K. Analysis of NR1-NR2A(N615K) (NR2A subunit with the p.N615K alteration) receptor currents revealed a loss of the Mg²(+) block and a decrease in Ca²(+) permeability. Our findings suggest that disturbances in the neuronal electrophysiological balance during development result in variable neurological phenotypes depending on which NR2 subunit of NMDA receptors is affected.
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Posterior glucose hypometabolism in Lafora disease: early and late FDG-PET assessment.
Epilepsia
PUBLISHED: 02-12-2010
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Establishing an early diagnosis of Lafora disease (LD) is often challenging. We describe two cases of LD presenting as myoclonus and tonic-clonic seizures, initially suggesting idiopathic generalized epilepsy. The subsequent course of the disease was characterized by drug-resistant myoclonic epilepsy, cognitive decline, and visual symptoms, which oriented the diagnosis toward progressive myoclonic epilepsy and, more specifically, LD. Early in the evolution in the first case, and before histopathologic and genetic confirmation of LD in both cases, [18]Fluorodeoxyglucose positron emission tomography (FDG-PET) revealed posterior hypometabolism, consistent with the well-known posterior impairment in this disease. This suggests that FDG-PET could help to differentiate LD in early stages from other progressive myoclonic epilepsies, but confirmation is required by a longitudinal study of FDG-PET in progressive myoclonic epilepsy.
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Inhibitory actions of the gamma-aminobutyric acid in pediatric Sturge-Weber syndrome.
Ann. Neurol.
PUBLISHED: 09-11-2009
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The mechanisms of epileptogenesis in Sturge-Weber syndrome (SWS) are unknown. We explored the properties of neurons from human pediatric SWS cortex in vitro and tested in particular whether gamma-aminobutyric acid (GABA) excites neurons in SWS cortex, as has been suggested for various types of epilepsies.
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LIS1-related isolated lissencephaly: spectrum of mutations and relationships with malformation severity.
Arch. Neurol.
PUBLISHED: 08-12-2009
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With the largest data set of patients with LIS1-related lissencephaly, the major cause of posteriorly predominant lissencephaly related to either LIS1 mutation or intragenic deletion, described so far, we aimed to refine the spectrum of neurological and radiological features and to assess relationships with the genotype.
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Deletion of YWHAE in a patient with periventricular heterotopias and pronounced corpus callosum hypoplasia.
J. Med. Genet.
PUBLISHED: 07-26-2009
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Malformations of cortical development are not rare and cause a wide spectrum of neurological diseases based on the affected region in the cerebral cortex. A significant proportion of these malformations could have a genetic basis. However, genetic studies are limited because most cases are sporadic and mendelian forms are rare.
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Transient brain magnetic resonance imaging hyperintensity in basal ganglia and brain stem of epileptic infants treated with vigabatrin.
J. Child Neurol.
PUBLISHED: 03-05-2009
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Vigabatrin is an antiepileptic drug that produces intramyelinic edema in several animal models. This study investigates the effect of vigabatrin on the developing human brain. The authors retrospectively blindly review 34 brain magnetic resonance imaging of 22 epileptic infants (age: 9 +/- 1 months) that received vigabatrin, focusing on the presence of hyperintensity on T2- and diffusion-weighted images. Patients treated with vigabatrin displayed significant magnetic resonance imaging hyperintensity of basal ganglia and brain stem (P < .001, Wilcoxon test). This hyperintensity was transient and maximal 3 to 6 months after the beginning of vigabatrin. Hyperintensity was independent from duration and type of epilepsy, and from the presence or absence of seizures. The authors conclude that vigabatrin treatment is associated with transient hypersignal of the basal ganglia and brain stem in epileptic infants. Such transient hyperintensity is likely to be age-dependent and time-dependent because it has never been observed in adult patients.
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[Brain maturation and epilepsy].
Rev Prat
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Eventually, glutamate and gamma-aminobutyric acid (GABA) are both excitatory; the first cortical synapses start to appear, some myelin is found in the cerebral hemispheres, and the long tracts are barely visible. The premature activation of N-methyl-D-aspartate (NMDA) transmission seems to generate neonatal myoclonic encephalopathy. Benign neonatal seizures and migrating partial seizures of infancy may result from an excessive or premature excitability in the deep layers. Benign rolandic epilepsy and continuous spikes and waves during slow sleep are associated with an excess of excitatory and inhibitory cortical synapses. West and Lennox-Gastaut syndromes are related to an age-dependent, diffuse cortical hyperexcitability; the clinical presentation depends on the age at onset, and spike synchronization is achieved by myelination. Idiopathic generalized epilepsy is driven by brain maturation, which induces a frontal hyperexcitability responsible for myoclonic-astatic seizures at an age comprised between that of infantile and juvenile myoclonic epilepsies. The extensive physiological time frame preceding the maturation of the hippocampal-neocortical system could explain the scarcity of cortical injuries resulting from a lesion in infants.
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Maturation of the human brain and epilepsy.
Handb Clin Neurol
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All features of childhood epilepsy are intimately related to brain development. The clinical EEG features of seizures are closely related to developmental changes in cell growth, synapse formation, and myelination. The immature brain is highly excitable due to the depolarizing effects of GABA, overexpression of glutamatergic receptors, and lack of efficient inhibitory control. Seizures have an age-specific effect on brain development.Whereas early life seizures rarely result in cell loss, they can induce changes in synapse organization and receptor physiology.
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Recurrent mutations in the CDKL5 gene: genotype-phenotype relationships.
Am. J. Med. Genet. A
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Mutations in the cyclin-dependent kinase-like 5 gene (CDKL5) have been described in epileptic encephalopathies in females with infantile spasms with features that overlap with Rett syndrome. With more than 80 reported patients, the phenotype of CDKL5-related encephalopathy is well-defined. The main features consist of seizures starting before 6 months of age, severe intellectual disability with absent speech and hand stereotypies and deceleration of head growth, which resembles Rett syndrome. However, some clinical discrepancies suggested the influence of genetics and/or environmental factors. No genotype-phenotype correlation has been defined and thus there is a need to examine individual mutations. In this study, we analyzed eight recurrent CDKL5 mutations to test whether the clinical phenotype of patients with the same mutation is similar and whether patients with specific CDKL5 mutations have a milder phenotype than those with other CDKL5 mutations. Patients bearing missense mutations in the ATP binding site such as the p.Ala40Val mutation typically walked unaided, had normocephaly, better hand use ability, and less frequent refractory epilepsy when compared to girls with other CDKL5 mutations. In contrast, patients with mutations in the kinase domain (such as p.Arg59X, p.Arg134X, p.Arg178Trp/Pro/Gln, or c.145?+?2T?>?C) and frameshift mutations in the C-terminal region (such as c.2635_2636delCT) had a more severe phenotype with infantile spasms, refractory epileptic encephalopathy, absolute microcephaly, and inability to walk. It is important for clinicians to have this information when such patients are diagnosed.
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Spectrum of pontocerebellar hypoplasia in 13 girls and boys with CASK mutations: confirmation of a recognizable phenotype and first description of a male mosaic patient.
Orphanet J Rare Dis
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Pontocerebellar hypoplasia (PCH) is a heterogeneous group of diseases characterized by lack of development and/or early neurodegeneration of cerebellum and brainstem. According to clinical features, seven subtypes of PCH have been described, PCH type 2 related to TSEN54 mutations being the most frequent. PCH is most often autosomal recessive though de novo anomalies in the X-linked gene CASK have recently been identified in patients, mostly females, presenting with intellectual disability, microcephaly and PCH (MICPCH).
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Atypical pyridoxine-dependent epilepsy due to a pseudoexon in ALDH7A1.
Mol. Genet. Metab.
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We report two siblings with atypical pyridoxine-dependant epilepsy, modest elevation of biomarkers, in which the open reading frame and the splice sites of ALDH7A1 did not show any mutations. Subsequent genetic analysis revealed a deep homozygous intronic mutation in ALDH7A1 resulting in two types of transcripts: the major transcript containing a pseudoexon, and the minor transcript representing the authentic spliced transcript. In future, this mutation may be targeted with antisense-therapy aiming at exclusion of the pseudoexon.
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Novel KCNQ2 and KCNQ3 Mutations in a Large Cohort of Families with Benign Neonatal Epilepsy: First Evidence for an Altered Channel Regulation by Syntaxin-1A.
Hum. Mutat.
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Mutations in the KCNQ2 and KCNQ3 genes encoding for Kv 7.2 (KCNQ2; Q2) and Kv 7.3 (KCNQ3; Q3) voltage-dependent K(+) channel subunits, respectively, cause neonatal epilepsies with wide phenotypic heterogeneity. In addition to benign familial neonatal epilepsy (BFNE), KCNQ2 mutations have been recently found in families with one or more family members with a severe outcome, including drug-resistant seizures with psychomotor retardation, EEG suppression-burst pattern (Ohtahara syndrome) and distinct neuroradiological features, a condition that was named "KCNQ2 encephalopathy". In the present paper, we describe clinical, genetic and functional data from 17 patients/families whose electro-clinical presentation was consistent with the diagnosis of BFNE. Sixteen different heterozygous mutations were found in KCNQ2, including 10 substitutions, three ins/del and three large deletions. One substitution was found in KCNQ3. Most of these mutations were novel, except for four KCNQ2 substitutions that were shown to be recurrent. Electrophysiological studies in mammalian cells revealed that homomeric or heteromeric KCNQ2 and/or KCNQ3 channels carrying mutant subunits with newly-found substitutions displayed reduced current densities. In addition, we describe, for the first time, that some mutations impair channel regulation by syntaxin-1A, highlighting a novel pathogenetic mechanism for KCNQ2-related epilepsies. This article is protected by copyright. All rights reserved.
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