Sahel Medical Journal

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


SA Balarabe1, MM Watila2,  
1 Department of Medicine, Usmanu Danfodiyo University Teaching Hospital, Sokoto, Nigeria
2 Department of Medicine, University of Maiduguri Teaching Hospital, Maiduguri, Nigeria

Correspondence Address:
S A Balarabe
Department of Medicine, Usmanu Danfodiyo University Teaching Hospital, P.M.B. 2370 Sokoto
Nigeria

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.



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;19:53-58


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 2024 Mar 28 ];19:53-58
Available from: https://www.smjonline.org/text.asp?2016/19/2/53/186038


Full Text

 Introduction



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



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



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



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



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.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

References

1Berg AT, Berkovic SF, Brodie MJ, Buchhalter J, Cross JH, van Emde Boas W, et al. Revised terminology and concepts for organization of seizures and epilepsies: Report of the ILAE commission on classification and terminology, 2005-2009. Epilepsia 2010;51:676-85.
2Panayiotopoulos CP. Idiopathic generalized epilepsies: A review and modern approach. Epilepsia 2005;46 Suppl 9:1-6.
3Proposal for revised classification of epilepsies and epileptic syndromes. Commission on classification and terminology of the international league against epilepsy. Epilepsia 1989;30:389-99.
4Gloor P. Generalized epilepsy with bilateral synchronous spike and wave discharge. New findings concerning its physiological mechanisms. Electroencephalogr Clin Neurophysiol Suppl 1978;(34)245-9.
5Tyvaert L, Chassagnon S, Sadikot A, LeVan P, Dubeau F, Gotman J. Thalamic nuclei activity in idiopathic generalized epilepsy: An EEG-fMRI study. Neurology 2009;73:2018-22.
6Brockmann K. The expanding phenotype of GLUT1-deficiency syndrome. Brain Dev 2009;31:545-52.
7Scheffer IE, Berkovic SF. Copy number variants – An unexpected risk factor for the idiopathic generalized epilepsies. Brain 2010;133(Pt 1):7-8.
8Sík A, Smith RL, Freund TF. Distribution of chloride channel-2-immunoreactive neuronal and astrocytic processes in the hippocampus. Neuroscience 2000;101:51-65.
9MacDonald BK, Cockerell OC, Sander JW, Shorvon SD. The incidence and lifetime prevalence of neurological disorders in a prospective community-based study in the UK. Brain 2000;123(Pt 4):665-76.
10Haug K, Warnstedt M, Alekov AK, Sander T, Ramírez A, Poser B, et al. Mutations in CLCN2 encoding a voltage-gated chloride channel are associated with idiopathic generalized epilepsies. Nat Genet 2003;33:527-32.
11Maljevic S, Krampfl K, Cobilanschi J, Tilgen N, Beyer S, Weber YG, et al. A mutation in the GABA(A) receptor alpha(1)-subunit is associated with absence epilepsy. Ann Neurol 2006;59:983-7.
12de Nijs L, Wolkoff N, Coumans B, Delgado-Escueta AV, Grisar T, Lakaye B. Mutations of EFHC1, linked to juvenile myoclonic epilepsy, disrupt radial and tangential migrations during brain development. Hum Mol Genet 2012;21:5106-17.
13Suzuki T, Delgado-Escueta AV, Aguan K, Alonso ME, Shi J, Hara Y, et al. Mutations in EFHC1 cause juvenile myoclonic epilepsy. Nat Genet 2004;36:842-9.
14Jara-Prado A, Martínez-Juárez IE, Ochoa A, González VM, Fernández-González-Aragón Mdel C, López-Ruiz M, et al. Novel myoclonin1/EFHC1 mutations in Mexican patients with juvenile myoclonic epilepsy. Seizure 2012;21:550-4.
15Liautard C, Scalmani P, Carriero G, de Curtis M, Franceschetti S, Mantegazza M. Hippocampal hyperexcitability and specific epileptiform activity in a mouse model of Dravet syndrome. Epilepsia 2013;54:1251-61.
16Chiu C, Reid CA, Tan HO, Davies PJ, Single FN, Koukoulas I, et al. Developmental impact of a familial GABAA receptor epilepsy mutation. Ann Neurol 2008;64:284-93.
17Bullmore E, Sporns O. The economy of brain network organization. Nat Rev Neurosci 2012;13:336-49.
18Griffa A, Baumann PS, Thiran JP, Hagmann P. Structural connectomics in brain diseases. Neuroimage 2013;80:515-26.
19Hagmann P, Sporns O, Madan N, Cammoun L, Pienaar R, Wedeen VJ, et al. White matter maturation reshapes structural connectivity in the late developing human brain. Proc Natl Acad Sci U S A 2010;107:19067-72.
20Fair DA, Cohen AL, Power JD, Dosenbach NU, Church JA, Miezin FM, et al. Functional brain networks develop from a “local to distributed” organization. PLoS Comput Biol 2009;5:e1000381.
21Liston C, Gan WB. Glucocorticoids are critical regulators of dendritic spine development and plasticity in vivo . Proc Natl Acad Sci U S A 2011;108:16074-9.
22Walsh MK, Lichtman JW.In vivo time-lapse imaging of synaptic takeover associated with naturally occurring synapse elimination. Neuron 2003;37:67-73.
23Xu T, Yu X, Perlik AJ, Tobin WF, Zweig JA, Tennant K, et al. Rapid formation and selective stabilization of synapses for enduring motor memories. Nature 2009;462:915-9.
24Nicholson JK, Lindon JC, Holmes E. 'Metabonomics': Understanding the metabolic responses of living systems to pathophysiological stimuli via multivariate statistical analysis of biological NMR spectroscopic data. Xenobiotica 1999;29:1181-9.
25Lin JJ, Mula M, Hermann BP. Uncovering the neurobehavioural comorbidities of epilepsy over the lifespan. Lancet 2012;380:1180-92.
26Hernan AE, Holmes GL, Isaev D, Scott RC, Isaeva E. Altered short-term plasticity in the prefrontal cortex after early life seizures. Neurobiol Dis 2013;50:120-6.
27Lin JJ, Riley JD, Hsu DA, Stafstrom CE, Dabbs K, Becker T, et al. Striatal hypertrophy and its cognitive effects in new-onset benign epilepsy with centrotemporal spikes. Epilepsia 2012;53:677-85.
28Pulsipher DT, Dabbs K, Tuchsherer V, Sheth RD, Koehn MA, Hermann BP, et al. Thalamofrontal neurodevelopment in new-onset pediatric idiopathic generalized epilepsy. Neurology 2011;76:28-33.
29Widjaja E, Zarei Mahmoodabadi S, Go C, Raybaud C, Chuang S, Snead OC, et al. Reduced cortical thickness in children with new-onset seizures. AJNR Am J Neuroradiol 2012;33:673-7.
30Pan PL, Song W, Yang J, Huang R, Chen K, Gong QY, et al. Gray matter atrophy in behavioral variant frontotemporal dementia: A meta-analysis of voxel-based morphometry studies. Dement Geriatr Cogn Disord 2012;33:141-8.
31Kaaden S, Helmstaedter C. Age at onset of epilepsy as a determinant of intellectual impairment in temporal lobe epilepsy. Epilepsy Behav 2009;15:213-7.
32Dombrowski SM, Hilgetag CC, Barbas H. Quantitative architecture distinguishes prefrontal cortical systems in the rhesus monkey. Cereb Cortex 2001;11:975-88.
33Goldberg EM, Coulter DA. Mechanisms of epileptogenesis: A convergence on neural circuit dysfunction. Nat Rev Neurosci 2013;14:337-49.
34Avanzini G, Manganotti P, Meletti S, Moshé SL, Panzica F, Wolf P, et al. The system epilepsies: A pathophysiological hypothesis. Epilepsia 2012;53:771-8.
35Ottman R, Hirose S, Jain S, Lerche H, Lopes-Cendes I, Noebels JL, et al. Genetic testing in the epilepsies – Report of the ILAE genetics commission. Epilepsia 2010;51:655-70.
36Lemke JR, Riesch E, Scheurenbrand T, Schubach M, Wilhelm C, Steiner I, et al. Targeted next generation sequencing as a diagnostic tool in epileptic disorders. Epilepsia 2012;53:1387-98.
37Koepp MJ, Woermann F, Savic I, Wandschneider B. Juvenile myoclonic epilepsy – Neuroimaging findings. Epilepsy Behav 2013;28 Suppl 1:S40-4.
38Meencke HJ, Janz D. Neuropathological findings in primary generalized epilepsy: A study of eight cases. Epilepsia 1984;25:8-21.
39Sisodiya SM, Free SL, Stevens JM, Fish DR, Shorvon SD. Widespread cerebral structural changes in patients with cortical dysgenesis and epilepsy. Brain 1995;118(Pt 4):1039-50.
40Woermann FG, Free SL, Koepp MJ, Sisodiya SM, Duncan JS. Abnormal cerebral structure in juvenile myoclonic epilepsy demonstrated with voxel-based analysis of MRI. Brain 1999;122(Pt 11):2101-8.
41O'Muircheartaigh J, Vollmar C, Barker GJ, Kumari V, Symms MR, Thompson P, et al. Focal structural changes and cognitive dysfunction in juvenile myoclonic epilepsy. Neurology 2011;76:34-40.