Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0014547 (focal epilepsy)
 1,627 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Kindling is a well documented model of acquired focal epilepsy and synaptic plasticity in the nervous system. Previous biochemical studies have indicated an increase in mGluR-mediated phosphoinositide hydrolysis in the amygdala or hippocampus of fully kindled animals. In this study we have used in situ hybridisation techniques to examine the mRNA expression of group I metabotropic glutamate receptors (mGluR1 and mGluR5 both linked to phosphoinositide hydrolysis) in the hippocampus of amygdala-kindled animals sacrificed 24 h, 7 days or 28 days following the last electrically evoked stage 5 seizure, and in implanted non-stimulated control rats. Results indicate an initial up-regulation in mGluR1 mRNA (expressed as percentage of control) bilaterally in the DG (35-40%) and CA3 (16-48%), and unilaterally in CA4 (12%) in the 24 h post-kindled group. In kindled animals studied 7 days after the last seizure, these changes were either reduced or had returned to control levels. By 28 days mGluR1 mRNA levels had returned to control levels, with only a persistent increase in expression unilaterally in the DG (14%). In contrast, an initial down-regulation in mGluR5 mRNA was observed bilaterally in CA4 (-45 and -25%) and CA1 (-46 and -45%), and unilaterally in DG and CA3 (-27 and -42% respectively) 24 h after the last kindled seizure. In the 7 and 28 day kindled groups significant alterations in expression of mGluR5 mRNA were still apparent. These data show that the mRNAs for mGluR1 and mGluR5 are differentially regulated by kindling, indicating that the expression of each of these receptors is under independent regulatory control. These perturbations in mRNA expression may contribute to kindling epileptogenesis but are unlikely to account for the maintenance of the kindled state.
Brain Res Mol Brain Res 1996 Dec 31
PMID:Altered expression of group I metabotropic glutamate receptors in the hippocampus of amygdala-kindled rats. 903 24

fos and jun belong to multigene families coding for transcription factors. These cellular immediate-early genes (IEGs) are thought to be involved in coupling neuronal excitation to changes of target gene expression. Immunocytochemistry with specific antisera was used to assess regional levels of five IEG-encoded proteins (c-FOS, FOS B, c-JUN, JUN B and JUN D) in a rat model of penicillin-induced focal epilepsy. To assess whether brain regions with post-ictal de novo transcription factor synthesis correspond to those areas with increased glucose metabolism, IEG expression patterns were compared with [14C]deoxyglucose autoradiography performed in a subset of animals. The results demonstrated marked induction of c-FOS, FOS B, c-JUN and JUN B but not JUN D in the cortical epileptic focus. Thereby, individual IEG-encoded proteins exhibited differential temporal and spatial expression patterns. Within the epileptic focus, IEG expression correlated with increased glucose metabolism. In contrast, IEG induction was not observed in brain areas distant from the epileptic focus that also demonstrated increased glucose metabolism, such as homotopic contralateral motor cortex and ipsilateral thalamic nuclei. These findings indicate that in focal epilepsy changes of the genetic programme are restricted to neurons of the epileptic focus. In contrast, the increased [14C]deoxyglucose metabolism in contralateral motor cortex and ipsilateral thalamus seems to indicate functional changes.
Brain Res Mol Brain Res 1997 Jun
PMID:Induction of FOS and JUN proteins during focal epilepsy: congruences with and differences to [14C]deoxyglucose metabolism. 919 Oct 92

The messenger ribonucleic acid (mRNA) of gap junction protein connexin 43 was quantified in the tetanus toxin rat model of focal epilepsy following injection of toxin into the left amygdala. Animals were monitored electrographically at weekly intervals with bilateral amygdala electrodes. Cohorts of 3 rats were sacrificed at weeks 1, 2, 3, 4, 6, 8, and 10, and bilateral regions containing the amygdala and posterior cerebral cortex were sampled, frozen, and later pooled for northern blot analysis. Spike generation was manifest in all animals during the first 4 wk followed by variable attenuation and cessation by 10 wk. Electrode implantation alone was shown by regression analysis to cause significant (p < 0.05) elevation of connexin mRNA in weeks 1-4. Injection of toxin diminished connexin mRNA expression in the amygdala when compared to electrode implantation alone. No trend in connexin mRNA expression was established over time in either amygdala or cerebral cortex in the acute epileptic or chronic postepileptic phase. No association between connexin 43 mRNA expression and the development of epileptogenicity was found in the context of a self-limiting animal model of focal epilepsy.
Mol Chem Neuropathol
PMID:Temporal profile of connexin 43 mRNA expression in a tetanus toxin-induced seizure disorder. 1034 69

A homozygous mutation of the CNTNAP2 gene has been associated with a syndrome of focal epilepsy, mental retardation, language regression and other neuropsychiatric problems in children of the Old Order Amish community. Here we report genomic rearrangements resulting in haploinsufficiency of the CNTNAP2 gene in association with epilepsy and schizophrenia. Genomic deletions of varying sizes affecting the CNTNAP2 gene were identified in three non-related Caucasian patients. In contrast, we did not observe any dosage variation for this gene in 512 healthy controls. Moreover, this genomic region has not been identified as showing large-scale copy number variation. Our data thus confirm an association of CNTNAP2 to epilepsy outside the Old Order Amish population and suggest that dosage alteration of this gene may lead to a complex phenotype of schizophrenia, epilepsy and cognitive impairment.
Mol Psychiatry 2008 Mar
PMID:CNTNAP2 gene dosage variation is associated with schizophrenia and epilepsy. 1764 49

Based on genomic rearrangements and copy number variations, the contactin-associated protein-like 2 gene (CNTNAP2) has been implicated in neurodevelopmental disorders such as Gilles de la Tourette syndrome, intellectual disability, obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, and attention deficit hyperactivity disorder. To explain the phenotypic pleiotropy of CNTNAP2 alterations, several hypotheses have been put forward. Those include gene disruption, loss of a gene copy by a heterozygous deletion, altered regulation of gene expression due to loss of transcription factor binding and DNA methylation sites, and mutations in the amino acid sequence of the encoded protein which may provoke altered interactions of the CNTNAP2-encoded protein, Caspr2, with other proteins. Also exome sequencing, which covers <0.2% of the CNTNAP2 genomic DNA, has revealed numerous single nucleotide variants in healthy individuals and in patients with neurodevelopmental disorders. In some of these disorders, disruption of CNTNAP2 may be interpreted as a susceptibility factor rather than a directly causative mutation. In addition to being associated with impaired development of language, CNTNAP2 may turn out to be a central node in the molecular networks controlling neurodevelopment. This review discusses the impact of CNTNAP2 mutations on its functioning at multiple levels of the combinatorial genetic networks that govern brain development. In addition, recommendations for genomic testing in the context of clinical genetic management of patients with neurodevelopmental disorders and their families are put forward.
Mol Syndromol 2015 Feb
PMID:Connecting the CNTNAP2 Networks with Neurodevelopmental Disorders. 2585 43

Numerous diverse biological pathways are dysregulated in the epileptic focus. Which of these pathways are most critical in producing the biological abnormalities that lead to epilepsy? Answering this question is key to identifying the primary causes of epilepsy and for discovering new therapeutic strategies with greater efficacy than currently available antiepileptics (AEDs). We have performed the largest genome-wide transcriptomic analysis to date comparing epileptic with normal human hippocampi. We have identified 118 differentially expressed and, for the first time, differentially connected pathways in the epileptic focus. Using network mapping techniques, we have shown that these dysregulated pathways, though seemingly disparate, form a coherent interconnected central network. Using closeness centrality analysis, we have identified that the most influential hub pathways in this network are signalling through G protein-coupled receptors, in particular opioid receptors, and their downstream effectors PKA/CREB and DAG/IP3. Next, we have objectively demonstrated that genetic association of gene sets in independent genome-wide association studies (GWASs) can be used to identify causally relevant gene sets: we show that proven causal epilepsy genes, which cause familial Mendelian epilepsy syndromes, are associated in published sporadic epilepsy GWAS results. Using the same technique, we have shown that central pathways identified (opioid receptor and PKA/CREB and DAG/IP3 signalling pathways) are genetically associated with focal epilepsy and, hence, likely causal. Published functional studies in animal models provide evidence of a role for these pathways in epilepsy. Our work shows that these pathways play a central role in human focal epilepsy and that they are important currently unexploited antiepileptic drug targets.
Hum Mol Genet 2015 Aug 01
PMID:Identifying the biological pathways underlying human focal epilepsy: from complexity to coherence to centrality. 2594 23

Prompted by the observations of juvenile myoclonic epilepsy (JME) in 22q11.2 deletion syndrome (22q11DS) and recurrent copy number variants in genetic generalized epilepsy (GGE), we searched for further evidence supporting a possible correlation of 22q11DS with GGE and with myoclonic seizures. Through routine diagnostics, we identified 3 novel individuals with the seemingly uncommon combination of 22q11DS and JME. We subsequently screened the literature for reports focussing on the epilepsy phenotype in 22q11DS. We additionally screened a database of 173 22q11DS patients and identified a fourth individual with JME as well as 2 additional cases with GGE. We describe 6 novel and 22 published cases with co-occurrence of 22q11DS and GGE. In many patients, GGE was associated with myoclonic seizures allowing for a diagnosis of JME in at least 6 individuals. Seventeen of the 173 22q11DS cases (10%) had a diagnosis of either focal or generalized epilepsy. In these cases, focal epilepsy could often be attributed to syndrome-associated hypocalcaemia, cerebral bleeds, or structural brain anomalies. However, the cause of GGE remained unclear. In this study, we describe and review 28 individuals with 22q11DS and GGE (especially JME), showing that both disorders frequently co-occur. Compared to the reported prevalence of 15-21%, in our case series only 10% of 22q11DS individuals were found to have epilepsy, often GGE. Since 22q11.2 does not contain convincing GGE candidate genes, we discuss the possibility of an aetiological correlation through a possibly disturbed interaction with the GABAB receptor.
Mol Syndromol 2016 Sep
PMID:Generalized Epilepsy and Myoclonic Seizures in 22q11.2 Deletion Syndrome. 2778 Oct 34

Intragenic deletions of the contactin-associated protein-like 2 gene (CNTNAP2) have been found in patients with Gilles de la Tourette syndrome, intellectual disability (ID), obsessive compulsive disorder, cortical dysplasia-focal epilepsy syndrome, autism, schizophrenia, Pitt-Hopkins syndrome, stuttering, and attention deficit hyperactivity disorder. A variety of molecular mechanisms, such as loss of transcription factor binding sites and perturbation of penetrance and expressivity, have been proposed to account for the phenotypic variability resulting from CNTNAP2 mutations. Deletions of both CNTNAP2 alleles produced truncated proteins lacking the transmembrane or some of the extracellular domains, or no protein at all. This observation can be extended to heterozygous intragenic deletions by assuming that such deletion-containing alleles lead to expression of a Caspr2 protein lacking one or several extracellular domains. Such altered forms of Capr2 proteins will lack the ability to bridge the intercellular space between neurons by binding to partners, such as CNTN1, CNTN2, DLG1, and DLG4. This presumed effect of intragenic deletions of CNTNAP2, and possibly other genes involved in connecting neuronal cells, represents a molecular basis for the postulated neuronal hypoconnectivity in autism and probably other neurodevelopmental disorders, including epilepsy, ID, language impairments and schizophrenia. Thus, CNTNAP2 may represent a paradigmatic case of a gene functioning as a node in a genetic and cellular network governing brain development and acquisition of higher cognitive functions.
Mol Syndromol 2017 May
PMID:Intragenic CNTNAP2 Deletions: A Bridge Too Far? 2858 33

During the cortical development, cells in the brain acquire somatic mutations that can be implicated in various neurodevelopmental disorders. There is increasing evidence that brain somatic mutations lead to sporadic form of epileptic disorders with previously unknown etiology. In particular, malformation of cortical developments (MCD), ganglioglioma (GG) associated with intractable epilepsy and non-lesional focal epilepsy (NLFE) are known to be attributable to brain somatic mutations in mTOR pathway genes and others. In order to identify such somatic mutations presenting as low-level in epileptic brain tissues, the mutated cells should be enriched and sequenced with high-depth coverage. Nevertheless, there are a lot of technical limitations to accurately detect low-level of somatic mutations. Also, it is important to validate whether identified somatic mutations are truly causative for epileptic seizures or not. Furthermore, it will be necessary to understand the molecular mechanism of how brain somatic mutations disturb neuronal circuitry since epilepsy is a typical example of neural network disorder. In this review, we overview current genetic techniques and experimental tools in neuroscience that can address the existence and significance of brain somatic mutations in epileptic disorders as well as their effect on neuronal circuitry.
Mol Cells 2018 Oct 31
PMID:Brain Somatic Mutations in Epileptic Disorders. 3035 90

Epilepsy is a diverse brain disorder, and the pathophysiology of its various forms and comorbidities is largely unknown. A recent machine learning method enables us to estimate an individual's "brain-age" from MRI; this brain-age prediction is expected as a novel individual biomarker of neuropsychiatric disorders. The aims of this study were to estimate the brain-age for various categories of epilepsy and to evaluate clinical discrimination by brain-age for (1) the effect of psychosis on temporal lobe epilepsy (TLE), (2) psychogenic nonepileptic seizures (PNESs) from MRI-negative epilepsies, and (3) progressive myoclonic epilepsy (PME) from juvenile myoclonic epilepsy (JME). In total, 1196 T1-weighted MRI scans from healthy controls (HCs) were used to build a brain-age prediction model with support vector regression. Using the model, we calculated the brain-predicted age difference (brain-PAD: predicted age-chronological age) of the HCs and 318 patients with epilepsy. We compared the brain-PAD values based on the research questions. As a result, all categories of patients except for extra-temporal lobe focal epilepsy showed a significant increase in brain-PAD. TLE with hippocampal sclerosis presented a significantly higher brain-PAD than several other categories. The mean brain-PAD in TLE with inter-ictal psychosis was 10.9 years, which was significantly higher than TLE without psychosis (5.3 years). PNES showed a comparable mean brain-PAD (10.6 years) to that of epilepsy patients. PME had a higher brain-PAD than JME (22.0 vs. 9.3 years). In conclusion, neuroimaging-based brain-age prediction can provide novel insight into or clinical usefulness for the diverse symptoms of epilepsy.
Mol Psychiatry 2019 Jun 03
PMID:Neuroimaging-based brain-age prediction in diverse forms of epilepsy: a signature of psychosis and beyond. 3116 Jun 92


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