ISSN 2415-3060 (print), ISSN 2522-4972 (online)
  • 31 of 57
УЖМБС 2020, 5(1): 210–218
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

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) 371K

  1. Fisher RS, Acevedo C, Arzimanoglou A, Bogacz A, Cross HJ, Elger ChE, et al. A practical clinical definition of еpilepsy. Epilepsia. 2014; 55(4): 475–82. PMID: 24730690.
  2. Gromov SA, Sivakova NA, Korsakova EA, Kataeva MF Epilepsiya: klassifikaciya remissij pripadkov bolezni, ih kliniko–psihologo–nejrofiziologicheskoe obosnovanie, voprosy diagnostiki i farmakoterapii. Obozrenie psihiatrii i medicinskoj psihologi. 2017; 3: 34–40.
  3. Berg AT, Shinnar S, Levy SR, Testa FM, Smith–Rapaport S, Beckerman B, et al. Two–year remission and subsequent relapse in children with newly diagnosed epilepsy. Epilepsia. 2001 Dec; 42(12): 1553–62. PMID: 11879366.
  4. Sillanpää M, Schmidt D. Prognosis of seizure recurrence after stopping antiepileptic drugs in seizure–free patients: A long–term population–based study of childhood–onset epilepsy. Epilepsy and Behavior. 2006; 8: 713–9. PMID: 16616648.
  5. Geerts A, Arts WF, Stroink H, Peeters E, Brouwer O, Peters B, et al. Course and outcome of childhood epilepsy: A 15–year follow–up of the follow–up of the Dutch Study of Epilepsy in Childhood. Epilepsia. 2010; 51(7): 1189–97. PMID: 20557350.
  6. Rogacheva TA. Zakonomernosti stanovleniya i techeniya remissii pri epilepsii. Abstr. Dr. Sci. (Med.). M; 2006. 319 s. [Russian]
  7. Löscher W, Klotz U, Zimprich F, Schmidt D. The clinical impact of pharmacogenetics on the treatment of epilepsy. Epilepsia. 2009 Jan; 50(1): 1–23. PMID:18627414.–1167.2008.01716.x
  8. Sánchez MB, Herranz JL, Leno C, Arteaga R, Oterino A, Valdizán EM, et al. Genetic factors associated with drug–resistance of epilepsy: relevance of stratification by patient age and aetiology of epilepsy. Seizure. 2010 Mar; 19(2): 93–101. PMID: 20064729.
  9. Lewis DF. 57 varieties: The human cytochromes P450. Pharmacogenomics. 2004; 5(3): 305–18. PMID: 15102545.
  10. Ingelman–Sundberg M. Human drug metabolising cytochrome P450 enzymes: Properties and polymorphisms. Naunyn Schmiedebergs Arch Pharmacol. 2004; 369(1): 89–104. PMID: 14574440.
  11. Anderson GD. Pharmacogenetics and enzyme induction/inhibition properties of antiepileptic drugs. Neurology. 2004; 63: 3–8. PMID: 15557548.
  12. Saruwatari J, Ishitsu T, Seo T, Shimomasuda M, Okada Y, Goto S, et al. The clinical impact of cytochrome P450 polymorphisms on the anti–epileptic drug therapy. Epilepsy Seizure. 2010; 3: 34–50.
  13. Kang P, Liao M, Wester MR, Leeder JS, Pearce RE, Correia MA. CYP3A4–Mediated carbamazepine (CBZ) metabolism: formation of a covalent CBZ–CYP3A4 adduct and alteration of the enzyme kinetic profile. Drug Metab Dispos. 2008; 36: 490–9. PMID: 18096676. PMCID: PMC2881839.
  14. Seo T, Nagata R, Ishitsu T, Murata T, Takaishi C, Hori M, et al. Impact of CYP2C19 polymorphisms on the efficacy of clobazam therapy. Pharmacogenomics. 2008; 9: 527–37. PMID: 18466100.
  15. Bajpai M, Roskos LK, Shen DD, Levy RH. Roles of cytochrome P450 2C9 and cytochrome P450 2C19 in the stereoselective metabolism of phenytoin to its major metabolite. Drug Metab Dispos. 1996; 24: 1401–3.
  16. Van der Weide J, Steijns LS, van Weelden MJ, de Haan K. The effect of genetic polymorphism of cytochrome P450 CYP2C9 on phenytoin dose requirement. Pharmacogenetics. 2001; 11: 287–91. PMID: 11434505.
  17. Silvado CE, Terra VC, Twardowschy CA. CYP2C9 polymorphisms in epilepsy: influence on phenytoin treatment. Pharmgenomics Pers Med. 2018; 11: 51–8. PMID: 29636628 PMCID: PMC5880189.
  18. Hung CC, Lin CJ, Chen CC, Chang CJ, Liou HH. Dosage recommendation of phenytoin for patients with epilepsy with different CYP2C9/CYP2C19 polymorphisms. Ther Drug Monit. 2004; 26: 534–40. PMID: 15385837.
  19. Goto S, Seo T, Murata T, Nakada N, Ueda N, Ishitsu T, et al. Population estimation of the effects of cytochrome P450 2C9 and 2C19 polymorphisms on phenobarbital clearance in Japanese. Ther Drug Monit. 2007; 29: 118–21. PMID: 17304159.
  20. Jiang D, Bai X, Zhang Q, Lu W, Wang Y, Li L, et al. Effects of CYP2C19 and CYP2C9 genotypes on pharmacokinetic variability of valproic acid in Chinese epileptic patients: nonlinear mixed–effect modeling. Eur J Clin Pharmacol. 2009; 65: 1187–93. PMID: 19756559.
  21. Monostory K,, Nagy A, Tóth K, Bűdi T, Kiss Á, Déri M, et al. Relevance of CYP2C9 Function in Valproate Therapy. Curr Neuropharmacol. 2019 Jan; 17(1): 99–106. PMID: 29119932. PMCID: PMC6341495.
  22. Hachad H, Ragueneau–Majlessi I, Levy RH. New antiepileptic drugs: review on drug interactions. Ther Drug Monit. 2002; 24: 91–103. PMID: 11805729.
  23. Orsini A, Esposito M, Perna D, Bonuccelli A, Peroni D, Striano P. Personalized medicine in epilepsy patients. Transl Genet Genom. 2018; 2: 16.
  24. Baulac M. Introduction to zonisamide. Epilepsy Res. 2006; 68: 3–9. PMID: 16413170.