Article

Genetics of epilepsy: Current status and perspectives

Department of Neuropsychiatry, Hirosaki University, Hirosaki 036-8562, Japan.
Neuroscience Research (Impact Factor: 2.15). 10/2002; 44(1):11-30. DOI: 10.1016/S0168-0102(02)00065-2
Source: PubMed

ABSTRACT Epilepsy affects more than 0.5% of the world's population and has a large genetic component. The most common human genetic epilepsies display a complex pattern of inheritance and the susceptibility genes are largely unknown. However, major advances have recently been made in our understanding of the genetic basis of monogenic inherited epilepsies. Progress has been particularly evident in familial idiopathic epilepsies and in many inherited symptomatic epilepsies, with the discovery that mutations in ion channel subunits are implicated, and direct molecular diagnosis of some phenotypes of epilepsy is now possible. This article reviews recent progress made in molecular genetics of epilepsy, focusing mostly on idiopathic epilepsy, and some types of myoclonus epilepsies. Mutations in the neuronal nicotinic acetylcholine receptor alpha4 and beta2 subunit genes have been detected in families with autosomal dominant nocturnal frontal lobe epilepsy, and those of two K(+) channel genes were identified to be responsible for underlying genetic abnormalities of benign familial neonatal convulsions. The voltage-gated Na(+) -channel (alpha1,2 and beta1 subunit), and GABA receptor (gamma2 subunit) may be involved in the pathogenesis of generalized epilepsy with febrile seizure plus and severe myoclonic epilepsy in infancy. Mutations of Ca(2+)-channel can cause some forms of juvenile myoclonic epilepsy and idiopathic generalized epilepsy. Based upon these findings, pathogenesis of epilepsy as a channelopathy and perspectives of molecular study of epilepsy are discussed.

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Available from: Sunao Kaneko, Aug 17, 2015
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    • "Epilepsy modeling is essential for understanding the basic mechanisms of the disease [3] [4] and for testing new antiepileptic drugs (AEDs). Currently, there are a variety of animal models of epilepsy, primarily rodent, and fly, fish, and worm models [11] [12] [13]. "
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    ABSTRACT: Epilepsy modeling is essential for understanding the basic mechanisms of the epileptic process. The Genetic Audiogenic Seizure Hamster (GASH:Sal) exhibits generalized tonic-clonic seizures of genetic origin in response to sound stimulation and is currently being validated as a reliable model of epilepsy. Here, we performed a pharmacological and neuroethological study using well-known and widely used antiepileptic drugs (AEDs), including phenobarbital (PB), valproic acid (VPA), and levetiracetam (LEV). The intraperitoneal administration of PB (5-20mg/kg) and VPA (100-300mg/kg) produced a dose-dependent decrease in GASH:Sal audiogenic seizure severity scores. The administration of LEV (30-100mg/kg) did not produce a clear effect. Phenobarbital showed a short plasmatic life and had a high antiepileptic effect starting at 10mg/kg that was accompanied by ataxia. Valproic acid acted only at high concentrations and was the AED with the most ataxic effects. Levetiracetam at all doses also produced sedation and ataxia side effects. We conclude that the GASH:Sal is a reliable genetic model of epilepsy suitable to evaluate AEDs.
    Epilepsy & Behavior 07/2013; 28(3):413-425. DOI:10.1016/j.yebeh.2013.05.028
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    • "An additional concern with arrhythmogenesis is that individuals with certain genetic backgrounds (including Kv-channel genotypes) can acquire it when administered with certain drugs (Anantharam et al., 2003). Furthermore, SNPs in Kv-channel genes also cause, or predispose individuals to, various neurological disorders including epilepsy (Kaneko et al., 2002), neuromyotonia (Poujois et al., 2006) and episodic ataxia (Scheffer et al., 1998), as well as other diseases, such as deafness (Kubisch et al., 1999). While not directly fatal, these disorders would still benefit from pre-symptomatic diagnosis and treatment. "
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    ABSTRACT: Non-synonymous single nucleotide polymorphisms (nsSNPs) in voltage-gated potassium (Kv) channels cause diseases with potentially fatal consequences in seemingly healthy individuals. Identifying disease-causing genetic variation will aid presymptomatic diagnosis and treatment of such disorders. NsSNP-effect predictors are hypothesized to perform best when developed for specific gene families. We, thus, created KvSNP: a method that assigns a disease-causing probability to Kv-channel nsSNPs. KvSNP outperforms popular non gene-family-specific methods (SNPs&GO, SIFT and Polyphen) in predicting the disease potential of Kv-channel variants, according to all tested metrics (accuracy, Matthews correlation coefficient and area under receiver operator characteristic curve). Most significantly, it increases the separation of the median predicted disease probabilities between benign and disease-causing SNPs by 26% on the next-best competitor. KvSNP has ranked 172 uncharacterized Kv-channel nsSNPs by disease-causing probability. KvSNP, a WEKA implementation is available at www.bioinformatics.leeds.ac.uk/KvDB/KvSNP.html. d.r.westhead@leeds.ac.uk Supplementary data are available at Bioinformatics online.
    Bioinformatics 06/2011; 27(16):2181-6. DOI:10.1093/bioinformatics/btr365
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    • "Current knowledge on the genetics of epileptic myoclonus is based mainly on disorders that exhibit myoclonus as a symptom (Kaneko et al., 2002; Grisar et al., 2006). In addition, animal models are being developed, to enable further study of these debilitating disorders (Vaarmann et al., 2006; Wang et al., 2007). "
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    ABSTRACT: Myoclonus is often observed in epilepsy. It is characterized by sudden involuntary shock-like movements of the body (myoclonic jerks, MJs). This study examined whether epileptic myoclonus was under genetic control. Inbred strains of mice were administered eight daily flurothyl exposures, a 28-day rest period, and a final flurothyl retest. For all trials, the latency to the first MJ (threshold) and the number of MJs (MJ#) were recorded. The inbred strains that we examined exhibited significant variability in initial myoclonic response, and myoclonus across the eight flurothyl exposures. C57BL/6J and DBA/2J mice displayed significantly different initial latencies to a MJ, MJ# preceding a generalized seizure (GS), and changes in MJ threshold and MJ# across the eight seizure trials. [C57BL/6J x DBA/2J] F1-hybrid mice showed an initial MJ threshold and decreases in MJ threshold over the eight trials, which were similar to C57BL/6J; however, F1-hybrids had an initial MJ# and trend in MJ# over the eight trials that were similar to DBA/2J. Decreases in MJ threshold and MJ# following multiple seizure trials, observed in C57BL/6J mice, were dependent on the expression of GSs and not on MJ occurrence. Our study is the first to document the potential for genetic heterogeneity of myoclonus in mice; we show that significant alterations in myoclonic behavior occur after GSs. These results indicate that multiple GSs affect MJ thresholds. An understanding of the genetics of myoclonus will be important for determination of the brain areas responsible for myoclonus as well as for identification of candidate genes.
    Epilepsy research 10/2009; 87(2-3):130-6. DOI:10.1016/j.eplepsyres.2009.08.003
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