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REVIEW ARTICLE
Year : 2016  |  Volume : 19  |  Issue : 2  |  Page : 53-58

Role of genetics in the etiopathogenesis of genetic generalized epilepsy: A review of current literature


1 Department of Medicine, Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria
2 Department of Medicine, University of Maiduguri Teaching Hospital, Maiduguri, Nigeria

Date of Web Publication12-Jul-2016

Correspondence Address:
S A Balarabe
Department of Medicine, Usmanu Danfodiyo University Teaching Hospital, P.M.B. 2370 Sokoto
Nigeria
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DOI: 10.4103/1118-8561.186038

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  Abstract 

Until recently, genetic generalized epilepsy (GGE) was believed to be of presumed genetic etiology with no identifiable genetic mutation or demonstrable epigenetic abnormality. A wide range of epileptic disorders has clue for an inherited susceptibility. Monogenic disorders associated with epilepsy mental retardation and structural brain lesion typified by heterotopias, tuberous sclerosis, and progressive myoclonus epilepsies account for about 1% of epilepsies. This review focuses on the role of genetic mutations and epigenetic rearrangements in the pathophysiologic mechanism of GGE. To achieve this; PubMed, EMBASE, and Google Scholar were systematically and comprehensively searched using keywords (“epilepsy” “juvenile myoclonic epilepsy (JME),” “typical absences,” “idiopathic generalized epilepsy,” “JME,” “juvenile absence epilepsy,” “childhood absence epilepsy” “generalized tonic-clonic seizure” “GTCS”). Most GGE has evidence of underlying genetic inheritance. Recent animal studies have shown that early detection and treatment of genetic generalized epilepsies can alter the phenotypic presentation in rodents. These findings suggest a critical period in epileptogenesis, during which spike-and-wave seizures can be suppressed, leading to chronic changes in the brain (epileptogenesis) and the preceding dysfunctions may, therefore, be targeted using therapeutic approaches that may either delay or inhibit the transition to active epileptic attack. The interplay between genetic mutations and epigenetic rearrangements play important roles in the development of GCE and that this process, especially at crucial developmental periods, is very susceptible to environmental modulations.

Keywords: Genetic generalized epilepsy, juvenile myoclonic epilepsy, magnetic resonance imaging, voxel-based morphometry


How to cite this article:
Balarabe S A, Watila M M. Role of genetics in the etiopathogenesis of genetic generalized epilepsy: A review of current literature. Sahel Med J 2016;19:53-8

How to cite this URL:
Balarabe S A, Watila M M. Role of genetics in the etiopathogenesis of genetic generalized epilepsy: A review of current literature. Sahel Med J [serial online] 2016 [cited 2018 Nov 19];19:53-8. Available from: http://www.smjonline.org/text.asp?2016/19/2/53/186038


  Introduction Top


Genetic generalized epilepsy (GGE) is a group of heterogeneous epileptic disorders that are either presumed to have a strong underlying genetic basis or the genetic component have already been identified. The genetic cause of some GGE types is known through inheritance does not always follow a simple monogenic mechanism.[1] GGE syndrome tends to present between early childhood and adolescence. Patients present clinically with myoclonic jerks, typical absences, and generalized tonic-clonic seizures (GTCS) alone or in varying combinations and severity.[2] Electroencephalographically, GGE is characterized by normal background activity and generalized discharges of spikes, polyspikes, or spikes/polyspikes-waves either ictally or interictally.[3] Some GGE syndromes have identified genes (e.g., SCN1A and Glut1) with clinical utility for early and accurate diagnosis. In addition, about five genes have been associated with autosomal dominant forms of juvenile myoclonic epilepsy (JME). The genes are implicated in primary channelopathies, and they comprised the following: Calcium channel sensor receptor (CASR), calcium channel beta4 subunit (CACNB4), gamma-aminobutyric acid (GABA) receptor delta subunit (GABRD), GABA receptor alpha one subunit (GABRα1), and myoclonin 1/one EF-hand containing gene (myoclonin1/EFHC1).


  Etiology of Genetic Generalized Epilepsy Top


GGE is characterized by electrographic evidence of widespread cortical hyperexcitability that manifests clinically as absences, myoclonic, or GTCS.[4] By definition patients with GGE do not show neuroimaging evidence of abnormal brain anatomy or a localized focus of seizure activity, rather there is widespread abnormal cortical activity characterized by generalized spike-and-wave (SW) or polyspike-wave discharges and seizures. The abnormal neuronal activity originates from dysfunction of thalamocortical or cortico-cortical communications that spread to the entire brain.[5] Atypical neuronal activity at a certain anatomic focus that is part of a larger thalamocortical network may be the initial site for rapid propagation of abnormal neuronal firing that results in generalized seizures.

GGEs are presumed to be genetically related, and they are often associated with mutations in ion channel subunits. Recent genetic data suggest that almost all the identified epilepsy monogenic disease-causing genes encode ion channel subunits (ligand-gated ion channels and voltage-gated ion channels). This led to the concept that the GGEs are a family of channelopathies.[6]

Role of genetics in the etiology of genetic generalized epilepsy

Since the first identification of CHRNA4 as the disease-causing gene implicated in Human Autosomal Dominant Nocturnal Frontal Lobe Epilepsy in 1995, rapid advances have been made in genetic studies related to GGE in the last two decades with the discovery of a number of genes that are implicated in GGE. Ion channel mutations play a principal role in the pathophysiologic mechanism of GGE syndromes.[6] However, GGE is complex and multifactorial, likely involving a combination of polygenic inheritance, environmental exposures, and gene–environment interactions. Molecular biologic techniques have revealed structural genomic copy number variations – deletion, insertions, duplications – associated with GGE that includes: Recurrent microdeletions at 15q11.2, 15q13.3, and 16p13.11.[7]

The chloride channel 2 gene

The chloride channel 2 (CLCN2) gene encodes a ubiquitous voltage-gated chloride channel protein, which widely expressed chloride channel in the brain that plays a significant role in maintaining the low intracellular Cl − concentration, which is essential for GABA-mediated inhibition.[8] Recent genomewide study revealed a susceptibility locus for common GGE subtypes on chromosome 3q26.[9] In 2003, Haug et al. found the CLCN2 mutations responsible for the common GGE subsyndromes including JME, childhood absence epilepsy and juvenile absence epilepsy, and epilepsy with GTCS on awakening.[10] The mutation causes loss of channels ability to lower the transmembrane chloride gradient essential for GABAergic inhibition.

Gamma aminobutyric acid Type A receptor subunit genes

Mutations in GABA Type A (GABAA) receptor subunit genes (GABRA1, GABRB3, GABRG2, and GABRD) have been found to be associated with genetic epilepsy syndromes that include JME and CAE.[11] Functional studies revealed that the mutant protein had no channel current, and the subunit remained docile in the cytoplasm and was not integrated into the plasma membrane, resulting in a complete loss of function.[11] This suggests the possibility that the reduction in GABAA receptor-mediated inhibition may result in a neuronal hyperexcitability that subsequently leads to epilepsy.

One EF-hand containing

The EFHC1 is 11 exons containing gene mapped to 6p12.2, and encodes a microtubule-associated protein, a protein with a Ca 2+-binding EF-hand motif which is involved in cell division and radial migration during cerebral corticogenesis.[12] Heterozygous variants of EFHC1 gene were reported to be responsible for JME, whereas homozygous mutation was associated with primary intractable epilepsy in infancy.[13],[14] In addition, recent findings suggest that mutation of EFHC1 altered mitotic spindle organization and interrupted radial and tangential migration by affecting the structure of radial glia and migrating neurons, thereby disrupting cerebral development and potentially producing morphological cerebral abnormalities on which epileptogenesis is believed to be established.[11],[13]

However, genetic studies and clinical evaluation cannot always fully explain genotype–phenotype correlations because they do not permit for conclusive inference on the functional effects of a mutation and its pathogenic mechanism(s). Therefore, functional analysis using experimental models is important in this regard. For example, experimental models have helped to identify pathogenic mechanisms of some epileptic syndromes (e.g., SCN1A- or KCNQ2/KCNQ3-related); particularly, experimental models of genetic epilepsy have made it possible to detect an early preepileptic time during which specific neuronal network dysfunctions are present without generating seizures.[15] This preepileptic period may represent epileptogenesis, and the preceding dysfunctions may, therefore, be targeted using therapeutic approaches that may either delay or inhibit the transition to active epileptic attack. These age-dependent periods may suggest specific developmental roles of some mutant proteins, but might also be due to age-related factors that influence the functional effects of mutations and possibly maintain disease progression. Identifying the pathogenic mechanisms functioning in the preepileptic period might provide targets for therapeutic approaches that prevent developmental defects and the associated epileptic seizures. Such an early intervention would be specifically important because seizures may trigger pathological changes that aggravate and sustain the epileptic condition or altered brain functions.[16]


  Pathophysiology Top


The structural architecture of the human brain is highly organized,[17] accomplished through a neatly arranged developmental process, with age-dependent changes that ensure maximal efficiency.[18],[19] Functional units within the brain are separated into specialized regions, that are subsequently integrated into a “global network.”[20] The outline of different brain regions and their connectivity are progressively changed into small anatomical domains that optimize synchronous local and general information processing. Studies have shown that the human brain has capability to undergo considerable functional and structural changes (plasticity) in utero and during development that persist in the adult life.[21] Recent evidence suggests that though established synapses and dendrites can be maintained for long periods of time, they can sometimes be eliminated or rewired depending on the environmental challenges and changes.[22] Life experience and behavior modifies brain architecture and function.[23] These changes in the brain can be detected by quantitative measurement of the dynamic multiparametric response of a living system to pathophysiological stimuli or genetic modification (metabolome).[24]

Neurological diseases with onset during critical period of cerebral maturation and development may have a potential adverse effect on the orderly neurodevelopmental process. This scenario is particularly important in childhood epilepsy.[25] However, the extent to which childhood epilepsies influence the brain network organization, and the mechanisms by which the organization of structural networks in the developing brain may be functionally altered and biased toward the generation of abnormal electrical activity are uncertain. The current proposition suggests that the formation of abnormal networks associated with epileptogenesis early in life leads to an interruption in normal cerebral network development.[26]

Studies have revealed that children with new-onset epilepsy have evidence of preexisting regional [27],[28] and diffuse [29],[30] changes in cerebral volume and connectivity well before the onset of their epilepsy, which suggests the role of developmental factors in the creation of the altered network. Additionally, early-life seizures are associated with greater changes in brain structural abnormalities compared with late-life onset seizures.[31] In animal studies, cortical morphometric characteristics that include: Structural folding, neuronal density, and overall cortical thickness, have predicted anatomical connections between different cortical regions.[32] Cumulatively, these findings suggest an adverse neurodevelopmental impact of childhood-onset epilepsy, with resultant reorganization of cerebral structure that may eventually lead to functional alteration and biased toward the generation of abnormal electrical activity that promotes chronic seizures (epileptogenesis).[33] Furthermore, since GGEs are presumed to have a primarily genetic etiology, one of the current hypotheses is that the functional impairments express malfunction of a set of neurons with mutated ion channels or synaptic structures. Newer morphological findings, in addition, indicate the existence of subtle anatomical impairments in the structures involved in the ictogenic networks.[33]

In a recent expert review, it was concluded that the notion of complete involvement of brain as suggested by generalized SW discharges on the scalp electroencephalography is not tenable and has been replaced by the concept of participation of widely distributed but selective parts of the frontal, parietal, and occipital cortex; the default mode network and parts of the thalamus in a resonance circuitry that can be triggered off from variable regions. This supports the concept of a trigger zone on the background of genetically mutated neurons within a given region of thalamocortical system that has a genetically determined susceptibility.[34] Important components of the thalamocortical circuitry include thalamic neurons, cortical pyramidal neurons, and the nucleus reticularis thalami (NRT). While the major synaptic connections of the circuit include glutamatergic fibers between neocortical pyramidal cells and NRT and GABAergic fibers from NRT neurons to the thalamic relay neurons, recurrent collateral GABAergic fibers from the NRT activate GABA(A) receptors on adjacent NRT neurons. Therefore, the NRT plays a crucial role in modulating the flow of information between the thalamus and cerebral cortex (thalamocortical network).


  Juvenile Myoclonic Epilepsy Top


In general, JME is the stereotype GGE syndrome that is thought to be genetically related epileptic disorder. About five genes have been associated with autosomal dominant forms of JME. The genes are implicated in primary channelopathies and they comprised of the following: CASR, CACNB4, GABRD, GABRα1, and myoclonin1/EFHC1. These findings from exome sequencing diagnostic techniques in JME suggest that the correlations between genotype and phenotype in genetic epilepsies are rapidly developing.[35],[36]

Abnormality of thalamocortical function is considered to be the most significant mechanism of JME, and like other GGE syndromes, JME is electrophysiologically characterized by features that show the involvement of the two cerebral hemispheres from the beginning of seizures.[37] Neuropathological studies revealed evidence of microdysgenesis in GGE, in the form of cortical and subcortical dystopic neurons and some other microscopic structural abnormalities. In addition, neuropsychological and behavioral studies have suggested subtle frontal lobe dysfunction that is, associated with certain personality profile. Recent improvement in neuroimaging techniques has facilitated the identification of subtle structural and functional abnormalities, that provides a means of unraveling the underlying mechanisms of JME and the comparative role of focal versus generalized dysfunction.[37]

Although visual examination of conventional magnetic resonance imaging (MRI) in patients with GGE appears normal, neuropathological autopsy assessment revealed evidence of gray and white matter microdysgenesis.[38] Additionally, quantitative MRI can demonstrate subtle relative changes in the cortical and subcortical matter in specified volume of interest, allowing a means of identifying structural changes not visible with high-resolution MRI.[39] This technique has been used to detect subtle but diffuse cerebral structural changes in patients with GGE.[40] About 40% of JME patients studied using volume of interest were found to have significant structural abnormalities. Moreover, when voxel-based statistical parametric mapping was employed in analyzing structural MRI data, patients with JME were found to have a significant increase in cortical gray matter in the mesial frontal lobes compared with healthy controls.[40]

The technique demonstrated abnormalities in the cortical gray matter of about 25% (5/20) of the JME patients studied;[40] four of whom had previously been reported to have widespread abnormalities using quantitative MRI method.[41] Specifically, two patients were found to have bilateral areas of increased gray matter volume: One had increased gray matter volume in the temporal posterior and the other in the mesioparietal region while the remaining three patients had areas of decreased gray matter volume: Two in the frontopolar region and one in the frontomesial area.[40] Reliable interpretation of both unilateral and bilateral voxel-based techniques findings, very much depend on the level of thresholding chosen for the analysis. In addition, structural imaging studies in JME consistently demonstrated subtle changes in the mesial frontal lobe among JME patients. Voxel-based morphometric studies based on T1-weighted MRI revealed both gray matter increases [40] and decreases.[41] This may reflect not only differences in image analysis methodology but also supports the presence of subtle structural changes in mesio-frontal areas.[37]


  Conclusion Top


Until recently, GGE was believed to be of presumed genetic etiology with no identifiable genetic mutation or demonstrable epigenetic abnormality. However, it has become clear that the interplay between genetic mutations and epigenetic rearrangements play an essential role in the disease development and that this process, especially at crucial developmental periods, is very susceptible to environmental modulations.[33],[35] Experimental studies have shown that early-life environment is probably one of the most important causal components in the etiology of some epileptic syndromes.[31] Furthermore, recent studies have shown that early detection and treatment of genetic epilepsy can alter the phenotypic presentation. These findings suggest a critical period in epileptogenesis during which SW seizures can be suppressed, leading to chronic changes in the brain. Consequently, better understanding and awareness of the pathogenesis of GGE may provide a roadmap for identification and primary prevention of such a “critical period” which could lead to suppression of symptoms later in life.

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Conflicts of interest

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