Phisiopatology of epilepsy: genetics and environment

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Phisiopatology of epilepsy: genetics and environment


Gretel Laura Rodriguez Orive1*
Sergio Antonio Cruz Hechavarria1
Iliana Machado Reyes1


1University of Las Tunas "Dr. Zoilo Marinello Vidaurreta". Las Tunas, Cuba.


*Author for correspondence. E-mail:



Introduction: Epilepsy is a group of chronic neurological syndromes derived from alterations in brain functions that present with recurrent paroxysmal crises triggered by abnormal electrical discharges.
Objective: describe the updated knowledge related to the genetic bases of the phisiophatology of epilepsy. Material and method: A bibliography revision was made .
Methods: analysis-synthesis, induction-decuction, historic-logic were used. Forty- three bibliographic references available at the virtual library of health.
Results: the mechanisms which causes electric shocks were described: a decrease of gabaergic inhibitor mechanisms, an increase of stimulating mechanisms mediated by aspartic and glutamic acid and alteration of the transmembrane conduction of sodium and calcium ions. Genes implicated in the neural ionic canal of sodium, potasium, chlorine, calcium(SCN1A, SCN1B, SNC2A, KCNQ2,KCNQ3, CLCN2, CACNA1H), with the receptors for the acetilcoline and GABA neurotransmitter: CHRNA4 and CHRNB2. The gen GRIA3 related to the eye-brain-renal syndrom or Lowe Syndrome. From the epigenetic mechanisms the methylation of DNA and the micro RNA in the epileptgenesis. The pharmacological effectivity according to the neurotrasmitter glutamic(stimulating): topiramate ,talampanel, ketamin; GABA(inhibitor) direct action: benzodiazepines (diazepam, clobazam) and barbiturates(phenobarbital, loreclezol,carisbamate); drugs with indirect action on GABA: acido valproico, tiagabina,vigabatrina (increase of the gabaergig tone by means of the irreversible and suicide inactivation of the enzyme responsable for the metabolism of GABA). Other drugs are: gabapentin, losigamona.
Conclusions: It is considered that the genetic bases of the phisiophatology of epilpsy are an important element to understand it is ethiophatogenic, new therapeutic approaches and for the discovery of new drugs.

Key words: epilepsy; genetic; phisiology.


Pathophysiology of epilepsy

The mechanisms that generate an electric discharge are: diminution of the gabaergic mechanisms, increase of the exitadores mechanisms mediated by aspartic and glutamic acid and an alteration of the transmembrane conduction of the sodium and calcium ions. The neurotransmitters that participate in the generation of seizures can be excitatory or inhibitory, the former open sodium and calcium channels such as glutamate and acetylcholine, and the inhibitors open the potassium and chloride channels like GABA.
The mechanisms of generation of crisis at the cellular level are related to the increase of excitation: (ionic: Ca and Na entry, neurotransmitters: glutamate and aspartate), the decrease of inhibition (ionic: entry of Cl and exit of K, neurotransmitters: GABA) and the modulation of gene expression (protein receptors).1

Neurotransmitters involved in epilepsy, genes and therapeutic management

The main precursors of Glutamate are glutamine and glucose and its function consists in the union to ionotropic (action on ion channels) and metabotropic receptors (coupled to G proteins). The ionotropic receptors are: AMPA, Kainate, NMDA.2,3

Sodium channel of the glutamatergic receptor

The AMPA receptors are associated to non-voltage dependent channels responsible for depolarizing currents (result of the entry of sodium to the neuron).

The different subtypes of AMPA receptors result from the combination of GluR1-4 peptide subunits that combine and form the channel pore, the selectivity of the channel is determined by amino acids, when there is a change between them this selectivity is lost and neuronal excitability increases . The expression of the amino acids and the greater or lesser proportion of subunits is genetically regulated by the GRIA2 gene and the GRIA3 corresponding to the GluR3 subunit have been localized mutations that are related to Lowe's oculo-cerebro-renal syndrome and Rasmussen's encephalitis (due to the presence of antibodies in the GluR3 subunit).

It is important to study this channel for the development of antiepileptic drugs such as Topiramate, its action depends on several mechanisms: AMPA receptor antagonist decreasing excitatory neurotransmission, and increases the activity of GABA through its receptor. 3,4

Sodium channel of the glutamatergic receptor kainate (KA)

The sodium channel of the KA receptor is similar to that of AMPA. Five high-affinity subunits GluR5, GluR6, GluR, KA1 and KA2 have been described. GluR5 and GluR6 are the most relevant for the CNS, because they are genetically regulated to let or not calcium pass, thus influencing the neurona's excitability. . In studies conducted in laboratory rats it has been shown that Topiramate is an antagonist of this receptor.4


Calcium channel of the glutamatergic NMDA receptor

This channel is activated by glutamate and voltage dependent, related to the Ca / Na channel. It has a glycine, polyamine, phenylcyclidine site and presents sites for the binding of glutamate and zinc. It consists of a subunit NR1 and several NR2, formed by segments that in turn form the pore of the channel. This channel is only activated when a neuronal depolarization occurs and by the combined action of glutamate and glycine opens the pore of the channel that is blocked by magnesium under normal conditions and calcium and sodium ions are produced that produce neuronal excitability. The NMDA receptor is of great importance in epileptogenesis as well as in the synchronization and propagation of electrical discharge, which is why one of the anticonvulsant strategies in humans is to competitively antagonize the glycine site of the channel; This has been achieved with Felbamate, although this produces several adverse reactions so it must be monitored. In other studies, Ketamine, a non-competitive NMDA receptor antagonist that blocks the flow of Ca and Na when combined with the phenylcyclidine site of this receptor, has been proposed.5


Metabotropic receptors

The metabotropic receptors are coupled to G proteins, activating the mechanism of second messengers. They are divided into three groups. Currently there is no agonist or antagonist of these receptors in clinical use for the reduction of epileptic seizures.4, 5

GABA: inhibitory neurotransmitter

It is a neurotransmitter that is synthesized from the decarboxylation of glutamate under the action of glutamate decarboxylase (GAD). It acts on different types of receptors: ionotropic (GABAa) and metabotropic (GABAb and GABAc) .4

GABAa receiver

The GABAa receptor is permeable to the chloride ion, causing a hyperpolarization of the neuronal membrane that inhibits nerve impulse conduction. Studies have altered the expression of the subunits that make up the GABA receptors (five subunits) in the hippocampus of these animals as well as in patients with temporal lobe epilepsy, which shows that epileptic seizures can be related to mutations in the subunits of the GABAa receptor.
Angelman syndrome is an example of the above, since this disease is related to a microdeletion of chromosome 15q 11-13 that encodes one of the subunits of the GABAa receptor and is associated with epilepsy and severe mental dysfunction.
Benzodiazepines (diazepam and clobazam), topiramate and retigabine have pharmacological action on the GABAa receptor, increasing its activity. Other drugs with action on this receptor are barbiturates, phenobarbital, loreclezol, felbamate and fluorofelbamate, carisbamate and neurosteroids (ganaxolone). 2,4

GABAb receiver

The GABAb receptor is metabotropic and located mainly in the spinal cord. The presynaptic receptors induce the decrease of neurotransmitter release due to the activation of the second messengers that inhibit the entry of calcium. However, the binding of an agonist to the postsynaptic GABAb receptor increases the potassium output to the extracellular medium, producing a slow inhibitory potential due to the hyperpolarization of the neurons.
The drug that acts on this receptor is baclofen (agonist), but it is not indicated as part of anticonvulsant treatments because it can worsen seizures.2,5

Several genes have been identified that are related to the epileptic syndromes:

-CHRNA4: first described mutation related to idiopathic epilepsy, was found in a family with autosomal dominant nocturnal frontal epilepsy.
-KCNQ2 and KCNQ3: first mutations described in generalized epilepsies and were found in families with benign neonatal familial epilepsy. These genes encode sequences of the subunits of voltage-dependent potassium channels.
-PRRT2: mutation related to benign familial infantile epilepsy.
-SCN1A (alpha-1 subunit of sodium neuronal channels triggered by voltage): its mutation produces a spectrum of convulsive manifestations that present an early onset of isolated febrile seizures and reach generalized epilepsy with febrile seizures plus, this being its phenotype serious.
-SCN1A (alpha-1 subunit of voltage-gated sodium neuronal channels): the mutation of this gene is related to severe myoclonic epilepsy in childhood or Dravet syndrome.
-SCN1B (alpha-1 subunit of voltage-triggered sodium neuronal channels): Voltage-triggered sodium channels are a family of proteins, each of which consists of subunits encoded by individual genes responsible for the initial phase of depolarization, which later produces an action potential.
-SCN2A (alpha-2 subunit of voltage-gated sodium neuronal channels): the mutation of this gene has been related to Generalized Epilepsy with Febrile Seizures plus classic (GEFS +)
-KCNQ2 and KCNQ3 (members two and three of the KQT surface of the voltage-dependent potassium channels): in a family with several members of different generations affected by the phenotype of the so-called Benign Familial Neonatal Seizures, linkage of the locus of the KCNQ2 gene. In addition mutations were found in the KCNQ3 gene.
-CLCN2 (calcium channels triggered by voltage type 2): the examination of several loci identified a locus of susceptibility in chromosome 3q26, site in which this gene is found, which was an obvious candidate. They are segregated into families with epileptic syndromes such as three: Typical Childhood Absence, Juvenile Absences, Juvenile Myoclonic Epilepsy and Tonic-Clonic Generalized Epilepsy with seizures upon awakening.(3,6,7,9)

Epigenetics and epilepsy

Rett syndrome is associated with mutations in the MECP2 gene that codes for the MBP subfamily, MeCP2, a protein that binds to specific sequences of methylated DNA and suppress their expression. The Angelman syndrome mentioned above, is a neurodegenerative disorder that occurs with epilepsy, is given by the genomic imprint of paternal origin (physiologically they present the CpG dinucleotides of methylated promoter zones). Another example of epimutation due to the regulation of this mechanism (epigenetics) is the reelin protein gene that produces alterations in the neuronal migration process, the synaptic plasticity and the maintenance of the granular structure of the granular cells of the hippocampus, the granular dispersion of the dentate nucleus of the hippocampus occurs in up to 50% of patients with sclerosis of the temporal lobe. In this epilepsy, the expression of DNMT1 and DNMT3 responsible for DNA methylation has also been studied as part of their pathogenesis. Studies have shown the importance of micro-RNA due to their potential as biomarkers and to the data they provide about the greater knowledge of the process of epileptogenesis.(Table)(7-10)




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3. Caldera, D., Juvenile Myoclonic Epilepsy, Neuropsychiatry Journal 81 (4) 2018, Available at:

4. García, P. et al., Neurotransmitters involved in epilepsy and its treatment, June, 2016, Final Degree Project, Complutense University, Faculty of Pharmacy.

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7. Lopes-Cendes, I., Genetic Aspects of Epilepsy: an updated view, Clinical Journal Condes-2013; 24 (6) 909-914.

8. Salgueiro-Pereira, A. et al., A two-hit story: Seizures and genetic mutation interaction sets phenotype severity in SCN1A epilepsies. Neurobiol Dis. May 2019; 125: 31-44. Doi: 10.1016/j.ndb.2019.01.006. Epub 2019 17 Jan.

9. Komulainen-Ebrahim J, et al. Novel variants GABRG2-related disorders.Seizure.2019 Mar 19; 69: 99-104

10. Wu T, et al. Mode of seizure inhibition by sodium chnnel blockers, an SV2A ligand, and an AMPA receptor antagonist in a rat amygdala kindling model.Epilepsy Res.2019.

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