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

Abstract

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

DNA methylation of the BRD2 promoter is associated with juvenile myoclonic epilepsy in Caucasians

“…JME was the first form of epilepsy for which a genetic locus was confirmed, demonstrating JME's genetic origin, and linkage and association analyses from different research groups over the past 3 decades have established BRD2 as a major genetic component for JME (see Santos et al for a review).…”

Genetic Landscape of Common Epilepsies: Advancing towards Precision in Treatment

“…GABRA1, EFHC1, CLCN2 are putative gene for JME while CACNB4 is not considered putative gene, because it has not been replicated [ 66 ]. rs3743123 (CX36), rs2029461 (GRM4), rs3918149 (BRD2) showed significant association with JME in more than one population [ 67 ]. Variation in EFHC1 is most commonly observed in families with JME [ 68 , 69 ].…”

“…The genetic variant, rs3918149 within the C-phosphate-G dinucleotides (CpG) island 76 of the BRD2 promoter region was revealed to be an epigenetic variant significantly associated with JME in the Caucasian population. Authors discussed that patients with JME show CpG76 hyper-methylation, possibly leading to decrease in BRD2 transcription [ 67 , 99 , 155 ]. In an animal model study, BRD2-null mutation (BRD2+/−) in mice causes a decrease in GABAergic neurons along the basal ganglia seizure-controlling pathway and GABA-synthesizing enzyme expression (GAD67), increasing seizure susceptibility and seizure development.…”

Targeting metabotropic glutamate receptors in the treatment of epilepsy: rationale and current status

“…In symptomatic WAG/Rij rats, systemic administration of the mGlu 4 receptor PAM, PHCCC, enhanced the incidence of SWDs [85]. Interestingly, polymorphic variants of GRM4, the gene encoding for the mGlu 4 receptor, have been associated with juvenile myoclonic epilepsy (JME), an epileptic syndrome belonging to the group of genetic generalized epilepsies and characterized, inter alia, by the occurrence of absence seizures [86][87][88].…”