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Genetic Variations Associated with Pharmacoresistant Epilepsy (Review)

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MOLECULAR MEDICINE REPORTS 21: 1685-1701, 2020 Genetic variations associated with pharmacoresistant epilepsy (Review) NOEMÍ CÁRDENAS-RODRÍGUEZ1*, LILIANA CARMONA-APARICIO1*, DIANA L. PÉREZ-LOZANO1,2, DANIEL ORTEGA-CUELLAR3, SAÚL GÓMEZ-MANZO4 and IVÁN IGNACIO-MEJÍA5,6 1Laboratory of Neuroscience, National Institute of Pediatrics, Ministry of Health, Coyoacán, Mexico City 04530; 2Department of Postgraduate of Medical, Dental and Health Sciences, Clinical Experimental Health Research, National Autonomous University of Mexico, Mexico City 04510; Laboratories of 3Experimental Nutrition and 4Genetic Biochemistry, National Institute of Pediatrics, Ministry of Health, Coyoacán, Mexico City 04530; 5Laboratory of Translational Medicine, Military School of Health Graduates, Lomas de Sotelo, Militar, Mexico City 11200; 6Section of Research and Graduate Studies, Superior School of Medicine, National Polytechnic Institute, Mexico City 11340, Mexico Received August 28, 2019; Accepted January 16, 2020 DOI: 10.3892/mmr.2020.10999 Abstract. Epilepsy is a common, serious neurological disorder the pathophysiological processes that underlie this common worldwide. Although this disease can be successfully treated human neurological disease. in most cases, not all patients respond favorably to medical treatments, which can lead to pharmacoresistant epilepsy. Drug-resistant epilepsy can be caused by a number of mecha- Contents nisms that may involve environmental and genetic factors, as well as disease- and drug-related factors. In recent years, 1. Introduction numerous studies have demonstrated that genetic variation is 2. Pharmacoresistant epilepsy involved in the drug resistance of epilepsy, especially genetic 3. Genetic variations associated with pharmacoresistant variations found in drug resistance-related genes, including epilepsy the voltage-dependent sodium and potassium channels genes, 4. The role of genetic variants in the diagnosis and treatment and the metabolizer of endogenous and xenobiotic substances of pharmacoresistant epilepsy genes. The present review aimed to highlight the genetic vari- 5. Clinical implications of genetic variants in pharmacoresistant ants that are involved in the regulation of drug resistance in epilepsy epilepsy; a comprehensive understanding of the role of genetic 6. Conclusions and future perspectives variation in drug resistance will help us develop improved strategies to regulate drug resistance efficiently and determine 1. Introduction Epilepsy is one of the most common neurological diseases worldwide and is considered a major public health Correspondence to: Dr Noemí Cárdenas‑Rodríguez, Laboratory problem (1,2). The International League Against Epilepsy of Neuroscience, National Institute of Pediatrics, Ministry of Health, (ILAE) has established that the term ‘epilepsy’ refers to a Av. Insurgentes Sur 3700 Letra C, Insurgentes‑Cuicuilco, Coyoacán, disease of the brain that meets any of the following conditions: Mexico City 04530, Mexico i) At least two non‑induced seizures, or reflexes, that occur E‑mail: [email protected] ≥24 h apart; ii) one non‑induced seizure, or reflex, and a risk of further seizures similar to the general recurrence risk (≥60%) *Contributed equally following two non-induced seizures that occur over the next Abbreviations: PWE, people with epilepsy; EMAS, epilepsy 10 years; or iii) the diagnosis of an epilepsy syndrome (3,4). with myoclonic-atonic seizures; EOEE, early onset epileptic Epilepsy is considered to be resolved when an individual with encephalopathies epilepsy has remained seizure-free for 10 years and without antiepileptic drug treatment for ≥5 years (4). Key words: epilepsy, pharmacoresistant, genetic, polymorphisms, For the most accurate study of epilepsy, the ILAE (5,6) has mutations epilepsy, clinical implications, personalized medicine, organized and classified seizures and several epilepsy types translational medicine as focal, generalized and of unknown onset, based on certain characteristics, including seizure type, electroencephalography (EEG) features, imaging studies, age-related features and 1686 CÁRDENAS-RODRÍGUEZ et al: GENETIC VARIATIONS ASSOCIATED WITH PHARMACORESISTANT EPILEPSY triggering factors, such as comorbidities and prognosis (6,7); required a second AED, and 3.7‑4% needed a third AED, which this classification involved the work of epileptologists, was administered either alone or in combination (17,18). To neurophysiologists and epilepsy researchers (6). summarize, Kwan and Brodie (17) observed that in a prospec- A previous study demonstrated that epileptic seizures are tive study of 525 PWE (age, 9‑93 years), 333 of them (63%) associated with several mechanisms that involve the glutamate remained seizure-free during AED administration and seizures excitotoxicity process, microglial activation, mitochondrial that did occur were more persistent in patients with symptom- dysfunction, degenerative processes, and the presence of reac- atic and cryptogenic epilepsy (40%) compared with those with tive oxygen species and oxidative stress (8). In addition, it has idiopathic epilepsy (26%). Moreover, among 470 previously previously been reported that certain regulatory processes are untreated patients, 222 of them (47%) became seizure‑free involved at the transcriptional level; for example, the nuclear during treatment with their first AED, 67 patients (14%) became transcription factor erythroid‑derived 2‑like 2 was revealed seizure-free during treatment with a second or third AED and to serve a role in epileptic seizures (9,10). A recent study 12 patients (3%) were controlled with two AEDs administered conducted by our group used microarray analysis in children together (17). Brodie et al (18) subsequently discovered that with epilepsy to demonstrate that those with epilepsy overex- patients have differential responses to AEDs; out of 1,098 PWE pressed genes that were related to the transcriptional factor (ages, 9‑93 years) studied, 749 of them (68%) were seizure‑free cAMP-response element binding protein (CREB) compared with AED monotherapy, but in 272 patients (25%), freedom from with normal children, in addition to significantly altered seizures was never attained. Moreover, <2% of patients became expression levels of genes involved in energy metabolism, seizure-free with the use of up to six or seven AEDs (18). In addi- redox balance and the immune response (11). The differential tion to the above findings, epidemiological studies conducted gene expression, particularly genes related to CREB, observed among children and adults have discovered that 20‑40% of in children before and after the administration of valproic PWE present with pharmacoresistant epilepsy (19-22), which acid indicated that the activity of antiepileptic drugs (AED) negatively impacts their quality of life because it is also associ- is dependent on target genes. These data suggested a role for ated with increases in psychiatric comorbidities and the risk of genetics in epilepsy development and highlighted the impor- premature death and social discrimination (23). tance of studying the genetic mechanisms associated with drug It is important to highlight that pharmacoresistant epilepsy resistance. This would provide an improved understanding may also cause serious socioeconomic problems. For instance, of the impact of pharmacological treatment on epilepsy and Argumosa and Herranz (24) evaluated the economic cost of in the patient's daily activities, of which both are influenced controlled and uncontrolled epilepsy in Spain (participants by: i) The patient's response to treatment; ii) the relationship were <14 years old) and reported that the mean annual cost between the number and type of seizures, and the modified of controlled epilepsy was $2,002.36 USD, whereas the cost transportation of proteins or their receptors due to the drug's of uncontrolled epilepsy was $5,348.50 USD; thus, uncon- activity and the presence of genetic variations; iii) the possible trolled epilepsy was 2.7 times more expensive compared with influence of the phenotypic characteristics of the patient in controlled epilepsy. Given the elevated costs of treatment, response to the treatment; iv) the impact of the presence of alternative therapeutic approaches, such as the ketogenic the genetic variants in the functionality of the transporting diet (25), high doses of steroids (26) and brain surgery (27) proteins and AED target proteins; v) the interference of the have all been implemented The ketogenic diet has proved potential alterations in the target protein on the mechanism of beneficial in PWE in which pharmacological and/or surgical action of the AED due to the presence of the variant; vi) the treatment is not effective; this diet is centered around a very influence of the inflammatory and immunological response; high‑fat and low‑carbohydrate intake, reducing carbohydrates vii) the predisposition to some of the different aspects of to <10% of used energy (90% of the total caloric intake comes epilepsy, including refractoriness or decreased sensitivity to from fat, 6% from protein and 4% from carbohydrates). These the AED effect; and viii) the result following the combination proportions trigger a systemic shift from glucose metabolism of several of these or other mechanisms (12-15). In accordance towards the metabolism of fatty acids, which yields ketone with the last point, the objective of the present review was to bodies that serve as the energy source to replace glucose in focus on describing
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  • Sex Differences in Glutamate Receptor Gene Expression in Major Depression and Suicide

    Sex Differences in Glutamate Receptor Gene Expression in Major Depression and Suicide

    Molecular Psychiatry (2015) 20, 1057–1068 © 2015 Macmillan Publishers Limited All rights reserved 1359-4184/15 www.nature.com/mp IMMEDIATE COMMUNICATION Sex differences in glutamate receptor gene expression in major depression and suicide AL Gray1, TM Hyde2,3, A Deep-Soboslay2, JE Kleinman2 and MS Sodhi1,4 Accumulating data indicate that the glutamate system is disrupted in major depressive disorder (MDD), and recent clinical research suggests that ketamine, an antagonist of the N-methyl-D-aspartate (NMDA) glutamate receptor (GluR), has rapid antidepressant efficacy. Here we report findings from gene expression studies of a large cohort of postmortem subjects, including subjects with MDD and controls. Our data reveal higher expression levels of the majority of glutamatergic genes tested in the dorsolateral prefrontal cortex (DLPFC) in MDD (F21,59 = 2.32, P = 0.006). Posthoc data indicate that these gene expression differences occurred mostly in the female subjects. Higher expression levels of GRIN1, GRIN2A-D, GRIA2-4, GRIK1-2, GRM1, GRM4, GRM5 and GRM7 were detected in the female patients with MDD. In contrast, GRM5 expression was lower in male MDD patients relative to male controls. When MDD suicides were compared with MDD non-suicides, GRIN2B, GRIK3 and GRM2 were expressed at higher levels in the suicides. Higher expression levels were detected for several additional genes, but these were not statistically significant after correction for multiple comparisons. In summary, our analyses indicate a generalized disruption of the regulation of the GluRs in the DLPFC of females with MDD, with more specific GluR alterations in the suicides and in the male groups.