Within the study, the primary task is to determine the significant genetical etiologies of the condition of epilepsy. With the relational focus between the occurrence of the condition and the physiological processes involved, the study determines the significant relationship of these genetic factors that causes or at least contributes to the occurrence of epilepsy in the perspective of neuropsychology. Considering different components that influence the manifestations of epilepsy, the study takes into account the possible factors contributing to their occurrences.
The study aims to determine the relationship of etiology against physiological factors in an effort to see possible linkage between these two pathophysiological components. Goals of the Study The goal of the study is to answer the main inquiry focusing on epilepsy and its linkage in the genetic factors that causes the manifestation of the condition. At the end of the study, the following inquiries should be answered appropriately: (a) how does genetic character of an individual influence the occurrence of epilepsy?
; (b) What are the genetic codes responsible for its occurrence and the process that links the overall physiological response? Background of the Study The condition of Generalized Epilepsy with Febrile Seizure Plus (GEFS+) is a known prominent heterogeneous autosomal dominant disorder that is present in family members under genetic influence. Such condition is characterized by multiple epilepsy phenotypes, which comprises of mycolonic, general tonic-clonic or partial seizures, and manifestation of febrile seizures as well.
The mutations in voltage-gated sodium channel (VGSC) have been linked to the occurrence of idiopathic epilepsy (Kamiya et. al. 2004). The general manifestations of GEFS+ are febrile seizures that possessed epileptic character. As according to assessments, patients with the said condition manifest severe deterioration of psychomotor development. According to the studies made (Barela et. al 2006; Kamiya et. al 2004; Spampanato et. al 2001), the genes that contribute to the occurrence of GEFS+ are SCN1A, SCN2A and SCN1B, and neurotransmitter gene class GABAa receptors. In addition, Barela et.
al. (2006) added the assessment obtained from families with identified GEFS+, which provided gene subunits, namely GABRG2 and GABRD, present in these families. The most prominent gene to cause the manifestations of GEFS+ is SCN1A, which is one of the nine paralogous genes in mammalian genome. The mutation on D1866Y of SCN1A had been considered as one of the main processes to initiate the febrile seizure manifestation. From the physiological perspective, a positive displacement of VDSC deactivates quickly, which endeavors possible case of hyperexcitablity (Spampanato et.
al. 2004). According to Barela et. al. (2006), the condition of GEFS+ can manifest febrile seizures beyond six years of age and can originate under simple to complex phenotypes. Hence, in this study, the center focuses more on the genetic basis of GEFS+ and the contributing factors that cause its occurrence. Since the study’s primary task is to determine the relationship between genetics and the pathological condition, these variables are analyzed mainly in neuropsychological point of view.
In the further sections, the study integrates and analyzes the study done previously in order to come up with justification in answering the statement of the problem. Discussion Methods and Findings Sharma (2005) pointed epilepsy as one of the most common neurological cases possibly affecting any individual regardless of age, gender or race. The study of Kamiya (2004) has utilized the idea of nonsense mutations of SCN2A, another etiological factor of genetic epilepsy, in 60 patients recruited with manifested childhood epilepsies.
Kamiya utilized mutation analysis, ECG recordings, Plasmid transfection and construction, Patch-clamp analysis, Electrical recording, Westernblot analysis and immunocytochemistry. His study aims to prove the relationship of SCN2A in patient demonstrating childhood epilepsy, which centers more on the dominant negative effect of mutant protein. In the study of Khalig (2006), the main focus revolved around the laboratory analysis of WT-SCN1A and R1648H in order to obtain biophysical characterization utilizing the tsA201 cells.
The study of Khalig utilized specific voltage-clamp protocols in providing the assessment in channel activation, inactivation, and recovery. In addition, he utilized calibration standards through multiple cells in order to test all cellular level similarities prior to the test. On the other hand, the study of the Spampanato (2004) focuses as well on the effects of the gene SCN1A in the occurrence of GERD+ in the highlight of D1866y gene subunit mutation.
In his study, he utilized expression and elextrophysiology, mutation detection, computational model and the use of NEURON to evaluate the relationship of inactivation through in the process of triggering or stimulating hyperexcitability. Results and Discussion As according to the results of the study by Kamiya (2004), the 20 out of 60 patients with childhood epilepsy are validated with no recurring SCN1A mutations; hence, the 20 patients have been screed for SCN2A mutation.
As according to the assessment made through the mentioned methodology, mutation analysis for SCN2A revealed significant manifestation of severe mental decline and seizure occurrences than those with SCN1A mutations. However, the study of Kamiya has only emphasized this SCN2A mutation in the conditions of intractable childhood epilepsy but not in GERD+. Although, he mentioned that the protein SCN2A is one of the proteins responsible for the occurred of this type of genetic epilepsy through the mutated function of Nav1. 2 channel.
On the other hand, in the study of Khalig (2004), he utilized Clampfit 9. 2, Originpro 7, and graphPa Prism 4 in order to evaluate the channel inactivation. He observed that most of the ion channel computation models depend on the quantitative date of the ionic currents. According to the results obtained, the R1648H manifested a surge during late single-channel openings (10 ms after voltage step), while WTSCN1A manifested an average of 200 progressive simulations during decreased conditions of late single-channel activity.
As supported by the findings from the Spampanato (2004), it is the gene SCN1A that is a candidate gene for the occurrence of GERD+. He added from his experiment of the Italian family pedigree that the individuals manifesting GERD+ with SCN1A mutation have shown significant heterozygous wild-type variance in exon 24. He added that the main key in determining the conditions of hyperexcitability (condition deemed to be responsible for the occurrence of epileptic seizures) is the inactivation of sodium channel and the voltage dependence.
This is supported by the earlier study of the Spampanato (2001) wherein he predicted that the mutation of DIV and DII results in different levels of excitability. According to him, the DIV mutation provides a quick recovery for the inactivation and decreased dependence of channel, while the DII mutations initiates an opposite reaction by slowing down the inactivation and increasing the frequency of channel dependence, which results to hypoexcitability. On the other hand, it is the condition of DIV mutation that causes the hyperexcitatbility.
He also added that it is the SCN1A the causes GERD+ seizures, while SCN2A is responsible for the occurrence of febrile seizure. Summary and Conclusion According to Khalig analysis, SCN1A deactivation is originated in a double-exponential time pattern. His study provided significant theory that relates to the fast sodium channel inactivation that is deemed critical in preventing excitation. Khalig mentions that slow inactivation may cause increase the duration of depolarization or possible, repetitive stimulation.
For this condition, Kamiya explained that the molecular biology of SCN2A, specifically on the subgene R102X, has undergone the nonsense-mediated RNA decay, which is an incidence of haploinsufficiency. As according to Spampanato, the D1866Y mutation in Nav1. 1 results in a positive displacement in the voltage dependence of sodium channel inactivation, which is somehow determined by the NEURON tool as responsible for causing neural hyperexcitability, which is determined as the primary cause of GERD+, the genetic epilepsy.
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