Association Analysis of <i>BRD2 (RING3)</i> and Epilepsy in a Dutch Population

Kovel, Carolien G.F. de; Pinto, Dalila; Haan, Gerrit-Jan de; Trenité, D G Kasteleijn-Nolst; Lindhout, Dick; Koeleman, Bobby P. C.

doi:10.1111/j.1528-1167.2007.01306.x

Cited by 14 publications

(10 citation statements)

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“…In relation to representativeness of the controls, fifty-six percent were either population–based or healthy volunteers[36,38–42,45,46,48,51–53,55,58,62–65,67,69–72,74,77,80,82,83] and forty-five percent were both population-based and hospital-based/healthy volunteers/blood donors[34,35,37,43,44,47,49,50,54,56,57,59–61,66,68,73,75,76,78,79,81]. Sixty four percent of control matched only one variable (age, gender or ethnicity) with cases[36–40,42–48,50–54,56,57,62,66,68,69,71,73,75–79,81,82]. Ninety-two percent clearly described diagnosis for JME[35–53,55–78,80,82,83].…”

Section: Resultsmentioning

confidence: 99%

“…For 5 polymorphisms, the positive association was not confirmed in independent studies (Table 1). For example, rs516535 in BRD 2, which had reported analysis in several background populations, showed a significant association with JME in Northern American population[83], but no association in larger samples of West European[54,60]. …”

Section: Resultsmentioning

confidence: 99%

“…Furthermore, BRD2 (but not rs3918149) was associated with photoparoxysmal response (PPR)[104]. Therefore, although the relationship between BRD2 and JME has not been replicated across some populations[54,60,77] convergent evidence supports BRD2 contributions to epileptogenesis. In fact, functional assays with heterozygous BRD2 knockout mice showed an increase in seizure susceptibility to flurothyl and the occurrence of spontaneous seizures in female mice[105].…”

Section: Discussionmentioning

confidence: 99%

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Genetic susceptibility in Juvenile Myoclonic Epilepsy: Systematic review of genetic association studies

et al. 2017

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BackgroundSeveral genetic association investigations have been performed over the last three decades to identify variants underlying Juvenile Myoclonic Epilepsy (JME). Here, we evaluate the accumulating findings and provide an updated perspective of these studies.MethodologyA systematic literature search was conducted using the PubMed, Embase, Scopus, Lilacs, epiGAD, Google Scholar and Sigle up to February 12, 2016. The quality of the included studies was assessed by a score and classified as low and high quality. Beyond outcome measures, information was extracted on the setting for each study, characteristics of population samples and polymorphisms.ResultsFifty studies met eligibility criteria and were used for data extraction. With a single exception, all studies used a candidate gene approach, providing data on 229 polymorphisms in or near 55 different genes. Of variants investigating in independent data sets, only rs2029461 SNP in GRM4, rs3743123 in CX36 and rs3918149 in BRD2 showed a significant association with JME in at least two different background populations. The lack of consistent associations might be due to variations in experimental design and/or limitations of the approach.ConclusionsThus, despite intense research evidence established, specific genetic variants in JME susceptibility remain inconclusive. We discussed several issues that may compromise the quality of the results, including methodological bias, endophenotype and potential involvement of epigenetic factors.PROSPERO registration numberCRD42016036063

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Genetic susceptibility in Juvenile Myoclonic Epilepsy: Systematic review of genetic association studies

et al. 2017

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“…In a second report, de Kovel et al [21] used a Dutch sample of IGE patients to test for association of three BRD2 SNPs with the IGE phenotype and, in a smaller sample, the JME phenotype. They found no evidence of association of the three SNPs with those phenotypes.…”

Section: Introductionmentioning

confidence: 99%

GABAergic Neuron Deficit As An Idiopathic Generalized Epilepsy Mechanism: The Role Of BRD2 Haploinsufficiency In Juvenile Myoclonic Epilepsy

et al. 2011

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Idiopathic generalized epilepsy (IGE) syndromes represent about 30% of all epilepsies. They have strong, but elusive, genetic components and sex-specific seizure expression. Multiple linkage and population association studies have connected the bromodomain-containing gene BRD2 to forms of IGE. In mice, a null mutation at the homologous Brd2 locus results in embryonic lethality while heterozygous Brd2+/− mice are viable and overtly normal. However, using the flurothyl model, we now show, that compared to the Brd2+/+ littermates, Brd2+/− males have a decreased clonic, and females a decreased tonic-clonic, seizure threshold. Additionally, long-term EEG/video recordings captured spontaneous seizures in three out of five recorded Brd2+/− female mice. Anatomical analysis of specific regions of the brain further revealed significant differences in Brd2+/− vs +/+ mice. Specifically, there were decreases in the numbers of GABAergic (parvalbumin- or GAD67-immunopositive) neurons along the basal ganglia pathway, i.e., in the neocortex and striatum of Brd2+/− mice, compared to Brd2+/+ mice. There were also fewer GABAergic neurons in the substantia nigra reticulata (SNR), yet there was a minor, possibly compensatory increase in the GABA producing enzyme GAD67 in these SNR cells. Further, GAD67 expression in the superior colliculus and ventral medial thalamic nucleus, the main SNR outputs, was significantly decreased in Brd2+/− mice, further supporting GABA downregulation. Our data show that the non-channel-encoding, developmentally critical Brd2 gene is associated with i) sex-specific increases in seizure susceptibility, ii) the development of spontaneous seizures, and iii) seizure-related anatomical changes in the GABA system, supporting BRD2's involvement in human IGE.

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“…(Galizia et al, 2015) BRD2 mutations have been linked to both PPR and JME in one study (Pal et al, 2003) but not in others. (Cavalleri et al, 2007;de Kovel et al, 2007;Lorenz et al, 2006) It is possible that both PPR and JME are caused by polygenetic mechanisms and that different combinations of genetic variations can lead to slight variations of the clinical phenotype. (Taylor et al, 2004) Our study is limited by the relatively small sample size and the fact that clinical EEG recordings offer ).…”

Section: Discussionmentioning

confidence: 99%

The topographical distribution of epileptic spikes in juvenile myoclonic epilepsy with and without photosensitivity

Bauer

Gorgels

Spetgens

et al. 2017

Clinical Neurophysiology

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The topographical distribution of epileptic spikes in juvenile myoclonic epilepsy with and without photosensitivity, Clinical Neurophysiology (2016), doi: http://dx.doi.org/10. 1016/j.clinph.2016.10.098 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AbstractObjective: Up to 30% of people with juvenile myoclonic epilepsy (JME) have photoparoxysmal responses (PPR). Recent studies report on structural and pathophysiological differences between people with JME with (JME+PPR) and without PPR (JME-PPR). We investigated whether electrophysiological features outside photic stimulation differ between these subtypes. Methods:We analysed EEG recordings of people with JME at a tertiary epilepsy centre and an academic hospital. Photosensitivity was assessed in a drug-naïve condition. We compared the occurrence and involvement of posterior electrodes for focal abnormalities and generalised spikewave activity in the EEG outside photic stimulation between JME+PPR and JME-PPR. Results:We included EEG recordings of 18 people with JME+PPR and 21 with JME-PPR. People with JME-PPR had less focal abnormalities in the posterior brain regions than people with JME+PPR (19% vs 55%, p<0.05). There was no difference in the distribution of generalised spike-wave activity between people with JME+PPR and JME-PPR. Conclusion:This study demonstrates electrophysiological correlates of the previously described structural and physiological differences between JME+PPR and JME-PPR.Significance: Findings support the hypothesis that posterior interictal EEG abnormalities reflect localised cortical hyperexcitability, which makes patients with JME more sensitive to photic stimuli.

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Association Analysis of BRD2 (RING3) and Epilepsy in a Dutch Population

Cited by 14 publications

References 8 publications

Genetic susceptibility in Juvenile Myoclonic Epilepsy: Systematic review of genetic association studies

Genetic susceptibility in Juvenile Myoclonic Epilepsy: Systematic review of genetic association studies

GABAergic Neuron Deficit As An Idiopathic Generalized Epilepsy Mechanism: The Role Of BRD2 Haploinsufficiency In Juvenile Myoclonic Epilepsy

The topographical distribution of epileptic spikes in juvenile myoclonic epilepsy with and without photosensitivity

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