Monogenic Epilepsies: Channelopathies, Synaptopathies, mTorpathies, and Otheropathies

Andrea D. Praticò; Raffaele Falsaperla; Agata Polizzi; Martino Ruggieri

doi:10.1055/s-0041-1727098

Journal of Pediatric Neurology, Table of Contents

Journal of Pediatric Neurology 2023; 21(03): 146-154
DOI: 10.1055/s-0041-1727098

Review Article

Monogenic Epilepsies: Channelopathies, Synaptopathies, mTorpathies, and Otheropathies

Andrea D. Praticò

¹Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy

,

Raffaele Falsaperla

²Unit of Pediatrics and Pediatric Emergency, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy

³Unit of Neonatal Intensive Care and Neonatology, University Hospital “Policlinico Rodolico-San Marco,” Catania, Italy

,

Agata Polizzi

⁴Chair of Pediatrics, Department of Educational Sciences, University of Catania, Catania, Italy

,

Martino Ruggieri

¹Unit of Rare Diseases of the Nervous System in Childhood, Department of Clinical and Experimental Medicine, Section of Pediatrics and Child Neuropsychiatry, University of Catania, Catania, Italy

› Author Affiliations

Abstract

Epilepsy has been historically defined as the recurrence of two or more seizures, together with typical electroencephalogram (EEG) changes, and significant comorbidities, including cardiac and autonomic changes, injuries, intellectual disability, permanent brain damage, and higher mortality risk. Epilepsy may be the consequence of several causes, including genetic anomalies, structural brain malformations, hypoxic–ischemic encephalopathy, brain tumors, drugs, and all contributing factors to the imbalance between excitatory and inhibitory neurons and modulatory interneurons which in turn provoke abnormal, simultaneous electric discharge(s) involving part, or all the brain. In the pregenetic, pregenomic era, in most cases, the exact cause of such neuronal/interneuronal disequilibrium remained unknown and the term “idiopathic epilepsy” was used to define all the epilepsies without cause. At the same time, some specific epileptic syndromes were indicated by the eponym of the first physician who originally described the condition (e.g., the West syndrome, Dravet syndrome, Ohtahara syndrome, and Lennox–Gastaut syndrome) or by some characteristic clinical features (e.g., nocturnal frontal lobe epilepsy, absence epilepsy, and epilepsy and mental retardation limited to females). In many of these occurrences, the distinct epileptic syndrome was defined mainly by its most relevant clinical feature (e.g., seizure semiology), associated comorbidities, and EEGs patterns. Since the identification of the first epilepsy-associated gene (i.e., CHRNA4 gene: cholinergic receptor neuronal nicotinic α polypeptide 4), one of the genes responsible for autosomal dominant nocturnal frontal lobe epilepsy (currently known as sleep-related hypermotor epilepsy) in 1995, the field of epilepsy and the history of epilepsy gene discoveries have gone through at least three different stages as follows: (1) an early stage of relentless gene discovery in monogenic familial epilepsy syndromes; (2) a relatively quiescent and disappointing period characterized by largely negative genome-wide association candidate gene studies; and (3) a genome-wide era in which large-scale molecular genetic studies have led to the identification of several novel epilepsy genes, especially in sporadic forms of epilepsy. As of 2021, more than 150 epilepsy-associated genes or loci are listed in the Online Mendelian Inheritance in Man database.

Keywords

epilepsy - genetics - monogenic - ion channels - synapsis proteins - mTOR - protein

Full Text

References

References
1 Fisher RS, Acevedo C, Arzimanoglou A. et al. ILAE official report: a practical clinical definition of epilepsy. Epilepsia 2014; 55 (04) 475-482
2 Falco-Walter JJ, Scheffer IE, Fisher RS. The new definition and classification of seizures and epilepsy. Epilepsy Res 2018; 139: 73-79
3 Scheffer IE, Berkovic S, Capovilla G. et al. ILAE classification of the epilepsies: Position paper of the ILAE Commission for Classification and Terminology. Epilepsia 2017; 58 (04) 512-521
4 Staley K. Molecular mechanisms of epilepsy. Nat Neurosci 2015; 18 (03) 367-372
5 Ruggieri M, Iannetti P, Pavone L. Delineation of a newly recognized neurocutaneous malformation syndrome with “cutis tricolor”. Am J Med Genet A 2003; 120A: 110-116
6 Gross RA. A brief history of epilepsy and its therapy in the Western Hemisphere. Epilepsy Res 1992; 12 (02) 65-74
7 Steinlein OK, Mulley JC, Propping P. et al. A missense mutation in the neuronal nicotinic acetylcholine receptor alpha 4 subunit is associated with autosomal dominant nocturnal frontal lobe epilepsy. Nat Genet 1995; 11 (02) 201-203
8 Helbig I, Heinzen EL, Mefford HC. ILAE Genetics Commission. Primer part 1-the building blocks of epilepsy genetics. Epilepsia 2016; 57 (06) 861-868
9 Helbig I, Tayoun AA. Understanding genotypes and phenotypes in epileptic encephalopathies. Mol Syndromol 2016; 7 (04) 172-181
10 Ellis CA, Petrovski S, Berkovic SF. Epilepsy genetics: clinical impacts and biological insights. Lancet Neurol 2020; 19 (01) 93-100
11 Amberger JS, Bocchini CA, Schiettecatte F, Scott AF, Hamosh A. OMIM.org: Online Mendelian Inheritance in Man (OMIM), an online catalog of human genes and genetic disorders. Nucleic Acids Res 2015; 43 (Database issue): D789-D798
12 Connolly MB. Dravet syndrome: diagnosis and long-term course. Can J Neurol Sci 2016; 43 (Suppl. 03) S3-S8
13 Dravet C. Les épilepsie grave de l’enfant. Vie Méd 1978; 8: 543-548
14 Musto E, Gardella E, Møller RS. Recent advances in treatment of epilepsy-related sodium channelopathies. Eur J Paediatr Neurol 2020; 24: 123-128
15 Parihar R, Ganesh S. The SCN1A gene variants and epileptic encephalopathies. J Hum Genet 2013; 58 (09) 573-580
16 Pratico AD, Falsaperla R, Ruggieri M, Corsello G, Pavone P. Prognostic challenges of SCN1A genetic mutations: report on two children with mild features. J Pediatr Neurol 2016; 14: 82-88
17 Mullen SA, Berkovic SF. ILAE Genetics Commission. Genetic generalized epilepsies. Epilepsia 2018; 59 (06) 1148-1153
18 Borlot F, Regan BM, Bassett AS, Stavropoulos DJ, Andrade DM. Prevalence of pathogenic copy number variation in adults with pediatric-onset epilepsy and intellectual disability. JAMA Neurol 2017; 74 (11) 1301-1311
19 International League Against Epilepsy Consortium on Complex Epilepsies. Genome-wide mega-analysis identifies 16 loci and highlights diverse biological mechanisms in the common epilepsies. Nat Commun 2018; 9 (01) 5269
20 Butler KM, da Silva C, Alexander JJ, Hegde M, Escayg A. Diagnostic yield from 339 epilepsy patients screened on a clinical gene panel. Pediatr Neurol 2017; 77: 61-66
21 Møller RS, Larsen LH, Johannesen KM. et al. Gene panel testing in epileptic encephalopathies and familial epilepsies. Mol Syndromol 2016; 7 (04) 210-219
22 Reif PS, Tsai MH, Helbig I, Rosenow F, Klein KM. Precision medicine in genetic epilepsies: break of dawn?. Expert Rev Neurother 2017; 17 (04) 381-392
23 Noebels JL. Single-gene models of epilepsy. Adv Neurol 1999; 79: 227-238
24 Szepetowski P. Genetics of human epilepsies: continuing progress. Presse Med 2018; 47 (03) 218-226
25 Oyrer J, Maljevic S, Scheffer IE, Berkovic SF, Petrou S, Reid CA. Ion channels in genetic epilepsy: from genes and mechanisms to disease-targeted therapies. Pharmacol Rev 2018; 70 (01) 142-173
26 Schorge S. Channelopathies go above and beyond the channels. Neuropharmacology 2018; 132: 1-2
27 Kim JB. Channelopathies. Korean J Pediatr 2014; 57 (01) 1-18
28 Wei F, Yan LM, Su T. et al. Ion channel genes and epilepsy: functional alteration, pathogenic potential, and mechanism of epilepsy. Neurosci Bull 2017; 33 (04) 455-477
29 Lerche H, Shah M, Beck H, Noebels J, Johnston D, Vincent A. Ion channels in genetic and acquired forms of epilepsy. J Physiol 2013; 591 (04) 753-764
30 Yilmaz M, Edgunlu TG, Yilmaz N. et al. Genetic variants of synaptic vesicle and presynaptic plasma membrane proteins in idiopathic generalized epilepsy. J Recept Signal Transduct Res 2014; 34 (01) 38-43
31 Fukata Y, Fukata M. Epilepsy and synaptic proteins. Curr Opin Neurobiol 2017; 45: 1-8
32 Griffith JL, Wong M. The mTOR pathway in treatment of epilepsy: a clinical update. Future Neurol 2018; 13 (02) 49-58
33 Nguyen LH, Mahadeo T, Bordey A. mTOR hyperactivity levels influence the severity of epilepsy and associated neuropathology in an experimental model of tuberous sclerosis complex and focal cortical dysplasia. J Neurosci 2019; 39 (14) 2762-2773
34 Wheless JW. Use of the mTOR inhibitor everolimus in a patient with multiple manifestations of tuberous sclerosis complex including epilepsy. Epilepsy Behav Case Rep 2015; 4: 63-66
35 de Calbiac H, Dabacan A, Marsan E. et al. Depdc5 knockdown causes mTOR-dependent motor hyperactivity in zebrafish. Ann Clin Transl Neurol 2018; 5 (05) 510-523
36 Myers CT, Mefford HC. Advancing epilepsy genetics in the genomic era. Genome Med 2015; 7: 91
37 Symonds JD, Zuberi SM, Johnson MR. Advances in epilepsy gene discovery and implications for epilepsy diagnosis and treatment. Curr Opin Neurol 2017; 30 (02) 193-199
38 Koch H, Weber YG. The glucose transporter type 1 (Glut1) syndromes. Epilepsy Behav 2019; 91: 90-93
39 Weber YG, Biskup S, Helbig KL, Von Spiczak S, Lerche H. The role of genetic testing in epilepsy diagnosis and management. Expert Rev Mol Diagn 2017; 17 (08) 739-750
40 Pavone P, Falsaperla R, Ruggieri M, Praticò AD, Pavone L. West syndrome treatment: new roads for an old syndrome. Front Neurol 2013; 4: 113
41 Meisler MH, O'Brien JE. Gene interactions and modifiers in epilepsy. In: Noebels JL, Avoli M, Rogawski MA, Olsen RW, Delgado-Escueta AV. eds. Jasper's Basic Mechanisms of the Epilepsies. 4th ed.. Bethesda MD: National Center for Biotechnology Information (US); 2012
42 Nagarajan RP, Patzel KA, Martin M. et al. MECP2 promoter methylation and X chromosome inactivation in autism. Autism Res 2008; 1 (03) 169-178
43 Boison D, Rho JM. Epigenetics and epilepsy prevention: the therapeutic potential of adenosine and metabolic therapies. Neuropharmacology 2020; 167: 107741
44 Mohandas N, Loke YJ, Mackenzie L. et al. Deciphering the role of epigenetics in self-limited epilepsy with centrotemporal spikes. Epilepsy Res 2019; 156: 106163
45 Hauser RM, Henshall DC, Lubin FD. The epigenetics of epilepsy and its progression. Neuroscientist 2018; 24 (02) 186-200
46 Kobow K, Blümcke I. Epigenetics in epilepsy. Neurosci Lett 2018; 667: 40-46
47 Guilhoto LM. Absence epilepsy: continuum of clinical presentation and epigenetics?. Seizure 2017; 44: 53-57
48 Ishiura H, Doi K, Mitsui J. et al. Expansions of intronic TTTCA and TTTTA repeats in benign adult familial myoclonic epilepsy. Nat Genet 2018; 50 (04) 581-590