Pharmacogenetics in Epilepsy and Refractory Epilepsy

Czornyj, Liliana; Auzmendi, Jerónimo; Lazarowski, Alberto

doi:10.1007/978-3-031-36526-3_10

Liliana Czornyj⁴,
Jerónimo Auzmendi^5,6 &
Alberto Lazarowski⁶

484 Accesses

Abstract

Pharmacogenomic studies in epilepsy are necessary due to the high prevalence of this disease and the high percentage of drug resistance phenotype. Several altered genes encode proteins involved in drug metabolism and drug transport (pharmacokinetics), function and expression of receptors, ion channels, metabolic regulatory proteins, or secondary messengers of signaling pathways (pharmacodynamics).

Despite the vast spectrum of antiseizure medications (ASMs) developed to date, refractory epilepsy remains consistently prevalent (30–40%). Since no ideal drug capable of curing all forms of epilepsy exists, the molecular identification of the genetic alterations responsible for each phenotype is the first step toward designing drugs capable of reversing the abnormality and thus developing personalized pharmacogenetic therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Subscribe and save

Springer+ Basic

$34.99 /Month

Get 10 units per month
Download Article/Chapter or eBook
1 Unit = 1 Article or 1 Chapter
Cancel anytime

Buy Now

Chapter: USD 29.95; Price excludes VAT (USA)

eBook: USD 179.99; Price excludes VAT (USA)

Softcover Book: USD 219.99; Price excludes VAT (USA)

Hardcover Book: USD 219.99; Price excludes VAT (USA)

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

From Genetic Testing to Precision Medicine in Epilepsy

Article 24 January 2020

Genetic Discoveries Drive Molecular Analyses and Targeted Therapeutic Options in the Epilepsies

Article 30 August 2015

Genetic Epilepsy

References

Almuqbil M, Go C, Nagy LL, et al. New paradigm for the treatment of glucose transporter 1 deficiency syndrome: low glycemic index diet and modified high amylopectin cornstarch. Pediatr Neurol. 2015;53:243–6. https://doi.org/10.1016/j.pediatrneurol.2015.06.018.
Article PubMed Google Scholar
Alvariza S, Fagiolino P, Vázquez M, et al. Chronic administration of phenytoin induces efflux transporter overexpression in rats. Pharmacol Rep. 2014;66:946–51. https://doi.org/10.1016/j.pharep.2014.06.007.
Article CAS PubMed Google Scholar
Amir RE, Van den Veyver IB, Wan M, et al. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23:185–8. https://doi.org/10.1038/13810.
Article CAS PubMed Google Scholar
Anderle P, Huang Y, Sadée W. Intestinal membrane transport of drugs and nutrients: genomics of membrane transporters using expression microarrays. Eur J Pharm Sci. 2004;21:17–24. https://doi.org/10.1016/s0928-0987(03)00169-6.
Article CAS PubMed Google Scholar
Auzmendi J, Palestro P, Blachman A, et al. Cannabidiol (CBD) inhibited rhodamine-123 efflux in cultured vascular endothelial cells and astrocytes under hypoxic conditions. Front Behav Neurosci. 2020;14:32. https://doi.org/10.3389/fnbeh.2020.00032.
Article CAS PubMed PubMed Central Google Scholar
Balestrini S, Sisodiya SM. Audit of use of stiripentol in adults with Dravet syndrome. Acta Neurol Scand. 2017;135:73–9. https://doi.org/10.1111/ane.12611.
Article CAS PubMed Google Scholar
Balestrini S, Sisodiya SM. Pharmacogenomics in epilepsy. Neurosci Lett. 2018;667:27–39. https://doi.org/10.1016/j.neulet.2017.01.014.
Article CAS PubMed PubMed Central Google Scholar
Bhattacharya A, Kaphzan H, Alvarez-Dieppa AC, et al. Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice. Neuron. 2012;76:325–37. https://doi.org/10.1016/j.neuron.2012.07.022.
Article CAS PubMed PubMed Central Google Scholar
Bi W, Glass IA, Muzny DM, et al. Whole exome sequencing identifies the first STRADA point mutation in a patient with polyhydramnios, megalencephaly, and symptomatic epilepsy syndrome (PMSE). Am J Med Genet A. 2016;170:2181–5. https://doi.org/10.1002/ajmg.a.3772.
Article CAS PubMed Google Scholar
Biswas M, Ershadian M, Shobana J, et al. Associations of HLA genetic variants with carbamazepine-induced cutaneous adverse drug reactions: an updated meta-analysis. Clin Transl Sci. 2022;15:1887–905. https://doi.org/10.1111/cts.13291.
Article CAS PubMed PubMed Central Google Scholar
Brzozowska N, Li KM, Wang XS, et al. ABC transporters P-gp and Bcrp do not limit the brain uptake of the novel antipsychotic and anticonvulsant drug cannabidiol in mice. PeerJ. 2016;4:e2081. https://doi.org/10.7717/peerj.2081.
Article CAS PubMed PubMed Central Google Scholar
Burnashev N, Szepetowski P. NMDA receptor subunit mutations in neurodevelopmental disorders. Curr Opin Pharmacol. 2015;20:73–82. https://doi.org/10.1016/j.coph.2014.11.008.
Article CAS PubMed Google Scholar
Calderon-Ospina CA, Galvez JM, Lopez-Cabra C, et al. Possible genetic determinants of response to phenytoin in a group of Colombian patients with epilepsy. Front Pharmacol. 2020;11:555. https://doi.org/10.3389/fphar.2020.00555.
Article CAS PubMed PubMed Central Google Scholar
Chen YY, Feng YY, Chen YN, et al. Association between ABCB1 C3435T polymorphism and antiepileptic drug resistance in epilepsy: an updated meta-analysis based on 62 studies. Int J Clin Pharmacol Ther. 2022;60:146–58. https://doi.org/10.5414/CP204045.
Article CAS PubMed Google Scholar
Cho CH. Frontier of epilepsy research—mTOR signaling pathway. Exp Mol Med. 2011;43:231–74. https://doi.org/10.3858/emm.2011.43.5.032.
Article CAS PubMed PubMed Central Google Scholar
Christians U, Schmitz V, Haschke M. Functional interactions between P-glycoprotein and CYP3A in drug metabolism. Expert Opin Drug Metab Toxicol. 2005;1:641–54. https://doi.org/10.1517/17425255.1.4.641.
Article CAS PubMed Google Scholar
Chung WH, Chang WC, Lee YS, et al. Genetic variants associated with phenytoin-related severe cutaneous adverse reactions. JAMA. 2014;312:525–34. https://doi.org/10.1001/jama.2014.7859.
Article PubMed Google Scholar
Cordon-Cardo C, O’Brien JP, Boccia J, et al. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. J Histochem Cytochem. 1990;38:1277–87. https://doi.org/10.1177/38.9.1974900.
Article CAS PubMed Google Scholar
Coughlin CR 2nd, Swanson MA, Spector E, et al. The genotypic spectrum of ALDH7A1 mutations resulting in pyridoxine dependent epilepsy: a common epileptic encephalopathy. J Inherit Metab Dis. 2019;42:353–61. https://doi.org/10.1002/jimd.12045.
Article CAS PubMed PubMed Central Google Scholar
Crino PB. mTOR signaling in epilepsy: insights from malformations of cortical development. Cold Spring Harb Perspect Med. 2015;5:a022442. https://doi.org/10.1101/cshperspect.a022442.
Article CAS PubMed PubMed Central Google Scholar
Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet. 2008;372:657–68. https://doi.org/10.1016/S0140-6736(08)61279-9.
Article CAS PubMed Google Scholar
Czornyj L, Lazarowski A. ABC-transporters as stem-cell markers in brain dysplasia/tumor epilepsies. Front Biosci (Landmark Ed). 2014;19:1425–35. https://doi.org/10.2741/4293.
Article PubMed Google Scholar
Czornyj L, Auzmendi J, Lazarowski A. Transporter hypothesis in pharmacoresistant epilepsies. Is it at the central or peripheral level? Epilepsia Open. 2022;7(Suppl 1):S34–46. https://doi.org/10.1002/epi4.12537.
Article PubMed Google Scholar
Davis BH, Beasley TM, Amaral M, et al. Pharmacogenetic predictors of cannabidiol response and tolerability in treatment-resistant epilepsy. Clin Pharmacol Ther. 2021;110:1368–80. https://doi.org/10.1002/cpt.2408.
Article CAS PubMed PubMed Central Google Scholar
De Giorgis V, Veggiotti P. GLUT1 deficiency syndrome 2013: current state of the art. Seizure. 2013;22:803–11. https://doi.org/10.1016/j.seizure.2013.07.003.
Article PubMed Google Scholar
De Leon J. The effects of antiepileptic inducers in neuropsychopharmacology, a neglected issue. Part II: Pharmacological issues and further understanding. Rev Psiquiatr Salud Ment. 2015;8:167–88. https://doi.org/10.1016/j.rpsm.2014.10.005.
Article PubMed Google Scholar
Depondt C. Pharmacogenetics in epilepsy treatment: sense or nonsense? Fut Med. 2008;5:123–31. https://doi.org/10.2217/17410541.5.2.123.
Article CAS Google Scholar
Ding J, Li X, Tian H, et al. SCN1A mutation—beyond Dravet syndrome: a systematic review and narrative synthesis. Front Neurol. 2021;12:743726. https://doi.org/10.3389/fneur.2021.743726.
Article PubMed PubMed Central Google Scholar
Doohan PT, Oldfield LD, Arnold JC, et al. Cannabinoid interactions with cytochrome P450 drug metabolism: a full-spectrum characterization. AAPS J. 2021;23:91. https://doi.org/10.1208/s12248-021-00616-7.
Article CAS PubMed Google Scholar
Ebid AH, Ahmed MM, Mohammed SA. Therapeutic drug monitoring and clinical outcomes in epileptic Egyptian patients: a gene polymorphism perspective study. Ther Drug Monit. 2007;29:305–12. https://doi.org/10.1097/FTD.0b013e318067ce90.
Article PubMed Google Scholar
Escalante-Santiago D, Feria-Romero IA, Ribas-Aparicio RM, et al. MDR-1 and MRP2 gene polymorphisms in mexican epileptic pediatric patients with complex partial seizures. Front Neurol. 2014;5:184. https://doi.org/10.3389/fneur.2014.00184.
Article PubMed PubMed Central Google Scholar
Feinshtein V, Erez O, Ben-Zvi Z, et al. Cannabidiol changes P-gp and BCRP expression in trophoblast cell lines. PeerJ. 2013;1:e153. https://doi.org/10.7717/peerj.153.
Article CAS PubMed PubMed Central Google Scholar
Frye RE, Donner E, Golja A, et al. Folinic acid-responsive seizures presenting as breakthrough seizures in a 3-month-old boy. J Child Neurol. 2003;18:562–9. https://doi.org/10.1177/08830738030180081001.
Article PubMed Google Scholar
Gaston TE, Bebin EM, Cutter GR, et al. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017;58:1586–92. https://doi.org/10.1111/epi.13852.
Article CAS PubMed Google Scholar
Geffrey AL, Pollack SF, Bruno PL, et al. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy. Epilepsia. 2015;56:1246–51. https://doi.org/10.1111/epi.13060.
Article CAS PubMed Google Scholar
Gospe SM Jr. Pyridoxine-Dependent Epilepsy–ALDH7A1. In: Adam MP, Everman DB, Mirza GM, et al (editors) GeneReviews® [Internet] Seattle (WA): University of Washington, Seattle; 2022. pp. 1993–2023. http://www.genereviews.org/.
Grønskov K, Brøndum-Nielsen K, et al. A nonsense mutation in FMR1 causing fragile X syndrome. Eur J Hum Genet. 2011;19:489–91. https://doi.org/10.1038/ejhg.2010.223.
Article CAS PubMed PubMed Central Google Scholar
Guevara N, Maldonado C, Uría M, et al. Role of CYP2C9, CYP2C19 and EPHX polymorphism in the pharmacokinetic of phenytoin: a study on Uruguayan Caucasian subjects. Pharmaceuticals (Basel). 2017;10:73. https://doi.org/10.3390/ph10030073.
Article CAS PubMed Google Scholar
Hallett L, Foster T, Liu Z. Burden of disease and unmet needs in tuberous sclerosis complex with neurological manifestations: systematic review. Curr Med Res Opin. 2011;27:1571–83. https://doi.org/10.1185/03007995.2011.586687.
Article PubMed Google Scholar
Hassel B, Rogne AG, Hope S. Intellectual disability associated with pyridoxine-responsive epilepsies: the need to protect cognitive development. Front Psych. 2019;10:116. https://doi.org/10.3389/fpsyt.2019.00116.
Article Google Scholar
Heath G, Colburn WA. An evolution of drug development and clinical pharmacology during the 20th century. J Clin Pharmacol. 2000;40:918–29. https://doi.org/10.1177/00912700022009657.
Article CAS PubMed Google Scholar
Hoeffer CA, Sanchez E, Hagerman RJ, et al. Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes Brain Behav. 2012;11:332–41. https://doi.org/10.1111/j.1601-183X.2012.00768.x.
Article CAS PubMed Google Scholar
Hoffmeyer S, Burk O, von Richter O, et al. Functional polymorphisms of the human multidrug-resistance gene: multiple sequence variations and correlation of one allele with P-glycoprotein expression and activity in vivo. Proc Natl Acad Sci U S A. 2000;97:3473–8. https://doi.org/10.1073/pnas.97.7.3473.
Article CAS PubMed PubMed Central Google Scholar
Hyland K, Buist NR, Powell BR, et al. Folinic acid-responsive seizures: a new syndrome? J Inherit Metab Dis. 1995;18:177–81. https://doi.org/10.1007/BF00711760.
Article CAS PubMed Google Scholar
Holland ML, Panetta JA, Hoskins JM, et al. The effects of cannabinoids on P-glycoprotein transport and expression in multidrug-resistant cells. Biochem Pharmacol. 2006;71:1146–54. https://doi.org/10.1016/j.bcp.2005.12.033.
Article CAS PubMed Google Scholar
Holland ML, Lau DT, Allen JD, et al. The multidrug transporter ABCG2 (BCRP) is inhibited by plant-derived cannabinoids. Br J Pharmacol. 2007;152:815–24. https://doi.org/10.1038/sj.bjp.0707467.
Article CAS PubMed PubMed Central Google Scholar
Irwin SA, Patel B, Idupulapati M, et al. Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. Am J Med Genet. 2001;98:161–7. https://doi.org/10.1002/1096-8628(20010115)98:2<161::aid-ajmg1025>3.0.co;2-b.
Article CAS PubMed Google Scholar
Jiang R, Yamaori S, Okamoto Y, et al. Cannabidiol is a potent inhibitor of the catalytic activity of cytochrome P450 2C19. Drug Metab Pharmacokinet. 2013;28:332–8. https://doi.org/10.2133/dmpk.dmpk-12-rg-129.
Article CAS PubMed Google Scholar
Jensen S, DiPaolo A, Lastella M, et al. Pharmacogenetics of ABCB1 and brain kinetics of ^99m-Tc-MIBI in epilepsy patients. Epilepsia. 2006;47(Suppl 3):88–9 (abstract).
Google Scholar
Johannessen CM, Reczek EE, James MF, et al. The NF1 tumor suppressor critically regulates TSC2 and mTOR. Proc Natl Acad Sci U S A. 2005;102:8573–8. https://doi.org/10.1073/pnas.0503224102.
Article CAS PubMed PubMed Central Google Scholar
Johannessen CM, Johnson BW, Williams SM, et al. TORC1 is essential for NF1-associated malignancies. Curr Biol. 2008;18:56–62. https://doi.org/10.1016/j.cub.2007.11.066.
Article CAS PubMed Google Scholar
Klepper J, Voit T. Facilitated glucose transporter protein type 1 (GLUT1) deficiency syndrome: impaired glucose transport into brain—a review. Eur J Pediatr. 2002;161:295–304. https://doi.org/10.1007/s00431-002-0939-3.
Article CAS PubMed Google Scholar
Klotz KA, Hirsch M, Heers M, et al. Effects of cannabidiol on brivaracetam plasma levels. Epilepsia. 2019;60:e74–7. https://doi.org/10.1111/epi.16071.
Article CAS PubMed Google Scholar
Klofas LK, Short BP, Snow JP, et al. DEPDC5 haploinsufficiency drives increased mTORC1 signaling and abnormal morphology in human iPSC-derived cortical neurons. Neurobiol Dis. 2020;143:104975. https://doi.org/10.1016/j.nbd.2020.
Article CAS PubMed PubMed Central Google Scholar
Kulkantrakorn K. Pyridoxine-induced sensory ataxic neuronopathy and neuropathy: revisited. Neurol Sci. 2014;35:1827–30. https://doi.org/10.1007/s10072-014-1902-6.
Article PubMed Google Scholar
Lau N, Feldkamp MM, Roncari L, et al. Loss of neurofibromin is associated with activation of RAS/MAPK and PI3-K/AKT signaling in a neurofibromatosis 1 astrocytoma. J Neuropathol Exp Neurol. 2000;59:759–67. https://doi.org/10.1093/jnen/59.9.759.
Article CAS PubMed Google Scholar
Lazarowski A, Sevlever G, Taratuto A, et al. Tuberous sclerosis associated with MDR1 gene expression and drug-resistant epilepsy. Pediatr Neurol. 1999;21:731–4. https://doi.org/10.1016/s0887-8994(99)00074-0.
Article CAS PubMed Google Scholar
Lazarowski A, Massaro M, Schteinschnaider A, et al. Neuronal MDR-1 gene expression and persistent low levels of anticonvulsants in a child with refractory epilepsy. Ther Drug Monit. 2004a;26:44–6. https://doi.org/10.1097/00007691-200402000-00010.
Article PubMed Google Scholar
Lazarowski A, Lubieniecki F, Camarero S, et al. Multidrug resistance proteins in tuberous sclerosis and refractory epilepsy. Pediatr Neurol. 2004b;30:102–6. https://doi.org/10.1016/S0887-8994(03)00407-7.
Article PubMed Google Scholar
Lazarowski AJ, Lubieniecki FJ, Camarero SA, et al. New proteins configure a brain drug resistance map in tuberous sclerosis. Pediatr Neurol. 2006;34:20–4. https://doi.org/10.1016/j.pediatrneurol.2005.06.008.
Article PubMed Google Scholar
Lazarowski A, Czornyj L. Genetics of epilepsy and refractory epilepsy. In: Dean M (ed) The genetic basis of human disease. Morgan & Claypool Life Sciences; 2013. p 1–119. https://doi.org/10.4199/C00073ED1V01Y201303GBD002.
Lazarowski A, Lubieniecki F, Camarero S, et al. Stem-cell marker CD34, multidrug resistance proteins P-gp and BCRP in SEGA. Receptor Clin Inv. 2014;1:e53. https://doi.org/10.14800/rci.53.
Article CAS Google Scholar
Li M, Zhou Y, Chen C, et al. Efficacy and safety of mTOR inhibitors (rapamycin and its analogues) for tuberous sclerosis complex: a meta-analysis. Orphanet J Rare Dis. 2019;14:39. https://doi.org/10.1186/s13023-019-1012-x.
Article PubMed PubMed Central Google Scholar
Liu L, Chen ZR, Xu HQ, et al. DEPDC5 variants associated malformations of cortical development and focal epilepsy with febrile seizure plus/febrile seizures: the role of molecular sub-regional effect. Front Neurosci. 2020;14:821. https://doi.org/10.3389/fnins.2020.00821.
Article PubMed PubMed Central Google Scholar
López-García MA, Feria-Romero IA, Fernando-Serrano H, et al. Genetic polymorphisms associated with antiepileptic metabolism. Front Biosci (Elite Ed). 2014;6:377–86. https://doi.org/10.2741/E713.
Article PubMed Google Scholar
López-García MA, Feria-Romero IA, Serrano H, et al. Influence of genetic variants of CYP2D6, CYP2C9, CYP2C19 and CYP3A4 on antiepileptic drug metabolism in pediatric patients with refractory epilepsy. Pharmacol Rep. 2017;69:504–11. https://doi.org/10.1016/j.pharep.2017.01.007.
Article CAS PubMed Google Scholar
Löscher W. The pharmacokinetics of antiepileptic drugs in rats: consequences for maintaining effective drug levels during prolonged drug administration in rat models of epilepsy. Epilepsia. 2007;48:1245–58. https://doi.org/10.1111/j.1528-1167.2007.01093.x.
Article CAS PubMed Google Scholar
Macdonald RL, Kang JQ, Gallagher MJ. Mutations in GABAA receptor subunits associated with genetic epilepsies. J Physiol. 2010;588:1861–9. https://doi.org/10.1113/jphysiol.2010.186999.
Article CAS PubMed PubMed Central Google Scholar
Marsan E, Baulac S. Review: Mechanistic target of rapamycin (mTOR) pathway, focal cortical dysplasia and epilepsy. Neuropathol Appl Neurobiol. 2018;44:6–17. https://doi.org/10.1111/nan.12463.
Article CAS PubMed Google Scholar
Mills PB, Camuzeaux SS, Footitt EJ, et al. Epilepsy due to PNPO mutations: genotype, environment and treatment affect presentation and outcome. Brain. 2014;137:1350–60. https://doi.org/10.1093/brain/awu051.
Article PubMed PubMed Central Google Scholar
Mirzaev KB, Fedorinov DS, Ivashchenko DV, et al. ADME pharmacogenetics: future outlook for Russia. Pharmacogenomics. 2019;20:847–65. https://doi.org/10.2217/pgs-2019-0013.
Article CAS PubMed Google Scholar
Moloney PB, Cavalleri GL, Delanty N. Epilepsy in the mTORopathies: opportunities for precision medicine. Brain Commun. 2021;3:fcab222. https://doi.org/10.1093/braincomms/fcab222.
Article CAS PubMed PubMed Central Google Scholar
Möller E, McIntosh JF, Van Slyke DD. Studies of urea excretion. II: Relationship between urine volume and the rate of urea excretion by normal adults. J Clin Invest. 1928;6:427–65. https://doi.org/10.1172/JCI100206.
Article PubMed PubMed Central Google Scholar
Mullen SA, Suls A, De Jonghe P, et al. Absence epilepsies with widely variable onset are a key feature of familial GLUT1 deficiency. Neurology. 2010;75:432–40. https://doi.org/10.1212/WNL.0b013e3181eb58b4.
Article CAS PubMed Google Scholar
Munisamy M, Al-Gahtany M, Tripathi M, et al. Impact of MTHFR (C677T) gene polymorphism on antiepileptic drug monotherapy in North Indian epileptic population. Ann Saudi Med. 2015;35:51–7. https://doi.org/10.5144/0256-4947.2015.51.
Article PubMed PubMed Central Google Scholar
Nasrin S, Watson CJW, Perez-Paramo YX, et al. Cannabinoid metabolites as inhibitors of major hepatic CYP450 enzymes, with implications for cannabis-drug interactions. Drug Metab Dispos. 2021;49:1070–80. https://doi.org/10.1124/dmd.121.000442.
Article CAS PubMed Google Scholar
Nguyen LH, Bordey A. Convergent and divergent mechanisms of epileptogenesis in mTORopathies. Front Neuroanat. 2021;15:664695. https://doi.org/10.3389/fnana.2021.664695.
Article CAS PubMed PubMed Central Google Scholar
Olson CO, Pejhan S, Kroft D, et al. MECP2 mutation interrupts nucleolin–mTOR–P70S6K signaling in Rett syndrome patients. Front Genet. 2018;9:635. https://doi.org/10.3389/fgene.2018.00635.
Article CAS PubMed PubMed Central Google Scholar
Operto FF, Mazza R, Pastorino GMG, et al. Epilepsy and genetics in Rett syndrome: a review. Brain Behav. 2019;9:e01250. https://doi.org/10.1002/brb3.1250.
Article PubMed PubMed Central Google Scholar
Ostendorf AP, Gutmann DH, Weisenberg JL. Epilepsy in individuals with neurofibromatosis type 1. Epilepsia. 2013;54:1810–4. https://doi.org/10.1111/epi.12348.
Article PubMed Google Scholar
Pal DK, Pong AW, Chung WK. Genetic evaluation and counseling for epilepsy. Nat Rev Neurol. 2010;6:445–53. https://doi.org/10.1038/nrneurol.2010.92.
Article PubMed Google Scholar
Parker WE, Orlova KA, Parker WH, et al. Rapamycin prevents seizures after depletion of STRADA in a rare neurodevelopmental disorder. Sci Transl Med. 2013;5:182ra53. https://doi.org/10.1126/scitranslmed.3005271.
Article CAS PubMed PubMed Central Google Scholar
Perelló MI, de Maria CA, Nogueira Arraes AC, et al. Severe cutaneous adverse drug reactions: diagnostic approach and genetic study in a Brazilian case series. Eur Ann Allergy Clin Immunol. 2022;54:207–17. https://doi.org/10.23822/EurAnnACI.1764-1489.193.
Article PubMed Google Scholar
Pierson TM, Yuan H, Marsh ED, et al. GRIN2A mutation and early-onset epileptic encephalopathy: personalized therapy with memantine. Ann Clin Transl Neurol. 2014;1:190–8. https://doi.org/10.1002/acn3.39.
Article CAS PubMed PubMed Central Google Scholar
Puffenberger EG, Strauss KA, Ramsey KE, et al. Polyhydramnios, megalencephaly and symptomatic epilepsy caused by a homozygous 7-kilobase deletion in LYK5. Brain. 2007;130:1929–41. https://doi.org/10.1093/brain/awm100.
Article PubMed Google Scholar
Rocha L, Frías-Soria CL, Ortiz JG, et al. Is cannabidiol a drug acting on unconventional targets to control drug-resistant epilepsy? Epilepsia Open. 2020;5:36–49. https://doi.org/10.1002/epi4.12376.
Article PubMed PubMed Central Google Scholar
Santiago-Castañeda C, Huerta de la Cruz S, Martínez-Aguirre C, et al. Cannabidiol reduces short- and long-term high glutamate release after severe traumatic brain injury and improves functional recovery. Pharmaceutics. 2022;14:1609. https://doi.org/10.3390/pharmaceutics14081609.
Article CAS PubMed PubMed Central Google Scholar
Sha LZ, Xing XL, Zhang D, et al. Mapping the spatio-temporal pattern of the mammalian target of rapamycin (mTOR) activation in temporal lobe epilepsy. PLoS One. 2012;7:e39152. https://doi.org/10.1371/journal.pone.0039152.
Article CAS PubMed Central Google Scholar
Shima A, Nitta N, Suzuki F, et al. Activation of mTOR signaling pathway is secondary to neuronal excitability in a mouse model of mesio-temporal lobe epilepsy. Eur J Neurosci. 2015;41:976–88. https://doi.org/10.1111/ejn.12835.
Article PubMed Google Scholar
Smolarz B, Makowska M, Romanowicz H. Pharmacogenetics of drug-resistant epilepsy (review of literature). Int J Mol Sci. 2021;22:11696. https://doi.org/10.3390/ijms222111696.
Article CAS PubMed PubMed Central Google Scholar
Socała K, Wyska E, Szafarz M, et al. Acute effect of cannabidiol on the activity of various novel antiepileptic drugs in the maximal electroshock- and 6 Hz-induced seizures in mice: pharmacodynamic and pharmacokinetic studies. Neuropharmacology. 2019;158:107733. https://doi.org/10.1016/j.neuropharm.2019.107733.
Article CAS PubMed Google Scholar
Strauss KA, Puffenberger EG, Huentelman MJ, et al. Recessive symptomatic focal epilepsy and mutant contactin-associated protein-like 2. N Engl J Med. 2006;354:1370–7. https://doi.org/10.1056/NEJMoa052773.
Article CAS PubMed Google Scholar
Steel D, Symonds J, Zuberi S, et al. Dravet syndrome and its mimics: beyond SCN1A. Epilepsia. 2017;58:1807–16. https://doi.org/10.1111/epi.13889.
Article CAS PubMed Google Scholar
Stockler S, Plecko B, Gospe SM Jr, et al. Pyridoxine dependent epilepsy and antiquitin deficiency: clinical and molecular characteristics and recommendations for diagnosis, treatment and follow-up. Mol Genet Metab. 2011;104:48–60. https://doi.org/10.1016/j.ymgme.2011.05.014.
Article CAS PubMed Google Scholar
Suls A, Dedeken P, Goffin K, et al. Paroxysmal exercise-induced dyskinesia and epilepsy is due to mutations in SLC2A1, encoding the glucose transporter GLUT1. Brain. 2008;131:1831–18-44. https://doi.org/10.1093/brain/awn113.
Switon K, Kotulska K, Janusz-Kaminska A, et al. Molecular neurobiology of mTOR. Neuroscience. 2017;341:112–53. https://doi.org/10.1016/j.neuroscience.2016.11.017.
Article CAS PubMed Google Scholar
Tang F, Hartz AMS, Bauer B. Drug-resistant epilepsy: multiple hypotheses, few answers. Front Neurol. 2017;8:301. https://doi.org/10.3389/fneur.2017.00301.
Article PubMed PubMed Central Google Scholar
Tate SK, Depondt C, Sisodiya SM, et al. Genetic predictors of the maximum dose patients receive during clinical use of the anti-epileptic drugs carbamazepine and phenytoin. Proc Natl Acad Sci U S A. 2005;102:5507–12. https://doi.org/10.1073/pnas.0407346102.
Article CAS PubMed PubMed Central Google Scholar
Tishler DM, Weinberg KI, Hinton DR, et al. MDR1 gene expression in brain of patients with medically intractable epilepsy. Epilepsia. 1995;36:1–6. https://doi.org/10.1111/j.1528-1157.1995.tb01657.x.
Article CAS PubMed Google Scholar
van Vliet EA, Forte G, Holtman L, et al. Inhibition of mammalian target of rapamycin reduces epileptogenesis and blood-brain barrier leakage but not microglia activation. Epilepsia. 2012;53:1254–63. https://doi.org/10.1111/j.1528-1167.2012.03513.x.
Article CAS PubMed Google Scholar
Vazquez SE, D’Giano C, Carpintiero S, et al. Increase ^99mTc-SESTAMIBI (MIBI) liver clearance could identified epileptic pharmacoresistant patients. A preliminary study. Annual Meeting of the American Epilepsy Society. Epilepsia. 2004;45:120 (abstract).
Google Scholar
Velasco-Parra H, Rodrı́guez L, González C, et al. Polimorfismo C3435T del gen ABCB1 (MDR1) en pacientes con epilepsia refractaria en tres centros de referencia nacional en Colombia. Medicina (Bogotá). 2011;33:249–59. ISSN: 0120-5498.
Google Scholar
Wang J, Lin ZJ, Liu L, et al. Epilepsy-associated genes. Seizure. 2017;44:11–20. https://doi.org/10.1016/j.seizure.2016.11.030.
Article CAS PubMed Google Scholar
Wong CSM, Yap DYH, Ip P, et al. HLA-B*15:11 status and carbamazepine-induced severe cutaneous adverse drug reactions in HLA-B*15:02 negative Chinese. Int J Dermatol. 2022;61:184–90. https://doi.org/10.1111/ijd.15792.
Article CAS PubMed Google Scholar
Yamaori S, Ebisawa J, Okushima Y, et al. Potent inhibition of human cytochrome P450 3A isoforms by cannabidiol: role of phenolic hydroxyl groups in the resorcinol moiety. Life Sci. 2011;88:730–6. https://doi.org/10.1016/j.lfs.2011.02.017.
Article CAS PubMed Google Scholar
Zhang B, Wong M. Pentylenetetrazole-induced seizures cause acute but not chronic mTOR pathway activation in rats. Epilepsia. 2012;53:506–11. https://doi.org/10.1111/j.1528-1167.2011.03384.x.
Article CAS PubMed PubMed Central Google Scholar
Zhu HJ, Wang JS, Markowitz JS, et al. Characterization of P-glycoprotein inhibition by major cannabinoids from marijuana. J Pharmacol Exp Ther. 2006;317:850–7. https://doi.org/10.1124/jpet.105.098541.
Article CAS PubMed Google Scholar

Download references

Author information

Authors and Affiliations

Neurology Service, Juan P. Garrahan National Children’s Hospital, Buenos Aires, Argentina
Liliana Czornyj
National Council for Scientific and Technical Research (CONICET) & Institute for Research in Physiopathology and Clinical Biochemistry (INFIBIOC), School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
Jerónimo Auzmendi
Institute for Research in Physiopathology and Clinical Biochemistry (INFIBIOC), School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
Jerónimo Auzmendi & Alberto Lazarowski

Authors

Liliana Czornyj
View author publications
You can also search for this author in PubMed Google Scholar
Jerónimo Auzmendi
View author publications
You can also search for this author in PubMed Google Scholar
Alberto Lazarowski
View author publications
You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Alberto Lazarowski .

Editor information

Editors and Affiliations

Pharmacobiology Department, Center for Research and Advanced Studies, México, Mexico
Luisa L. Rocha
Institute for Research in Physiopathology and Clinical Biochemistry (INFIBIOC), School of Pharmacy and Biochemistry, University of Buenos Aires, Buenos Aires, Argentina
Alberto Lazarowski
Department of Neurology and Neurosurgery, Escola Paulista de Medicina, Federal University of São Paulo, São Paulo, Brazil
Esper A. Cavalheiro

Rights and permissions

Reprints and permissions

Copyright information

About this chapter

Cite this chapter

Czornyj, L., Auzmendi, J., Lazarowski, A. (2023). Pharmacogenetics in Epilepsy and Refractory Epilepsy. In: Rocha, L.L., Lazarowski, A., Cavalheiro, E.A. (eds) Pharmacoresistance in Epilepsy. Springer, Cham. https://doi.org/10.1007/978-3-031-36526-3_10

Download citation

DOI: https://doi.org/10.1007/978-3-031-36526-3_10
Published: 30 August 2023
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-36525-6
Online ISBN: 978-3-031-36526-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)

Publish with us

Policies and ethics