ISSN 2415-3060 (print), ISSN 2522-4972 (online)
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JMBS 2020, 5(1): 210–218
https://doi.org/10.26693/jmbs05.01.210
Clinical Medicine

Investigation of Connection of Polymorphism Genes of the Cytochrome P450 System and the Course of Resistant Epilepsy in Children (Clinical–Pharmacogenetic Comparison)

Tantsura L. M. 1, Pylypets O. Yu. 1, Tantsura Ye. O. 2, Tretiakov D. V. 1
Abstract

In order to find out the connection between the polymorphism of P450 cytochrome genes and the course of resistant epilepsy in children (first of all, with the loss of achieved control), we conducted investigation of the frequency of polymorphisms of cytochrome P450 system genes CYP2C9, CYP2C19 and CYP3A4 in children with resistant forms of epilepsy and clinical–pharmacogenetic comparisons. Material and methods. 116 children with truly resistant epilepsy aged from 11 months to 18 years were examined comprehensively (boys – 67, girls – 49). In the course of study we used: clinical anamnestic; clinical and neurological; clinical and psychopathological; neurophysiological (electroencephalographic) methods, method of neuroimaging (nuclear magnetic resonance imaging of the brain); genetic (allelespecific polymerase–chain reaction); methods of mathematical statistics. The duration of epilepsy in children ranged from 7 months to 17 years, the age of onset of epilepsy ranged from several days from birth to 13 years. Results and discussion. The selection of alleles for pharmacogenetic research was based on literature sources on the role of these polymorphisms in antiepileptic drugs metabolism, population data on their prevalence in various regions and countries both in healthy volunteers and in patients with epilepsy, we investigated the carrier of the following alleles: CYP2C9*1, CYP2C9*2, CYP2C9*3, CYP2C19*1, CYP2C19*2, CYP2C19*3, CYP3A4*1, CYP3A4*1B. The presence of gene polymorphisms was found in 75 children (64.65%), with isolated CYP3A4 polymorphisms in 5 children (12.05%), CYP2C9 in 17 children (14.65%), CYP2C19 – in 39 children (33.62%) of the total patient group. In 14 cases (12.06%) we found a combination of multiple gene polymorphisms in one child. In the process of observation, the phenomenon of "non–motivated" loss of control of seizure attacks (without the influence of any provocative factors) was recorded. Clinical examples are presented to illustrate this phenomenon. We conducted the comparison of a number of clinical and paraclinical parameters between a group of children with and without established gene mutations. The formed groups did not differ in such indicators as age, gender composition, frequency and types of attacks, in general, no significant differences were found in most indicators. However, side effects of therapy were observed significantly more frequently (p<0.05) in the group of patients with detected gene polymorphisms than in the group without gene mutations, with this being true for such indicators as severe side effects and aggravation of seizures, when it was not only about the cancelation of the antiepileptic drugs, which caused an undesirable side reaction, but also about helping patients in the hospital. The phenomenon of "non–motivated" loss of seizure control in patients with established gene mutations was also observed more frequently (p<0.05). The difference between the groups in the frequency of non–severe side effects was not significant (p>0.05). The identified differences are arguments in favor for the role of the investigated gene polymorphisms in the metabolism of antiepileptic drugs, which is clinically implemented (due to instability, fluctuations in antiepileptic drugs concentrations) in the form of extraneous effects, first of all, severe side effects, and loss of control of attacks, which are not related to external factors. Conclusion. The obtained results showed that patients with epilepsy in the presence of polymorphisms of genes of the cytochrome P450 system should be performed: more often, in comparison with children with no polymorphisms, clinical examinations and electroencephalographic picture control; a detailed survey of patients and their parents and relatives on the recurrence of seizures and/or "new" types of epileptic paroxysms; obligatory correction of antiepileptic therapy, provided that negative dynamics of electroencephalographic picture indicators were detected (especially the appearance of typical epileptic patterns in patients with previously achieved normalization of the electroencephalographic picture), even in the absence of any paroxysmal disorders clinic.

Keywords: children, resistant epilepsies, genes polymorphism, P450 cytochrome

Full text: PDF (Ukr) 3.69M

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