Epilepsies occur in 0.5 to 1% of the population, with about half starting in childhood and at least 50% having genetic causes. The ILAE recommends that epilepsies previously referred to as idiopathic be renamed “genetic epilepsies”, while epilepsies that occur due to other genetic syndromes or chromosomal abnormalities can be classified as “non-syndromic epilepsies”. Next generation sequencing (NGS) is suitable for sequencing many potentially causative genes, while chromosomal and microarray analyses may be indicated for certain forms of epilepsy and additional symptoms.
Frequency
Epilepsies occur with a frequency of 0.5 to 1%; almost half of these begin in childhood.
Causes
At least 50% of epilepsies are genetic, with the cause being multifactorial or polygenic in most cases. Only 1 to 2% of so-called idiopathic epilepsies are monogenic. The ILAE (International League Against Epilepsy) proposes that epilepsies previously referred to as idiopathic should be renamed “genetic epilepsies”.
Idiopathic (genetic) epilepsies can be contrasted with symptomatic epilepsies that occur, for example, secondarily as a result of a congenital brain malformation (e.g., migration disorder), as part of a superordinate genetic syndrome (e.g., Angelman syndrome, Rett syndrome, tuberous sclerosis) or in the case of chromosomal imbalances (e.g., ring chromosome 20 or 14, microdeletion 15q13.3, 15q11.2, 16p13.11, additional marker chromosome 15 including the region 15q11.2 and others). According to the revised terminology of the ILAE, these epilepsies would be classified as “non-syndromic epilepsies”.
Diagnosis
Due to the clinical and genetic heterogeneity, next generation sequencing (NGS) is a particularly suitable diagnostic method for epilepsies, as it enables the sequencing of many potentially causative genes in a single examination. NGS can also be useful when examining the parents of a patient with a dominant new mutation to clarify the inheritance and thus the risk of recurrence, as in some families the causative variant has been detected in mosaic form in one parent and NGS can detect mosaics better than classic Sanger sequencing.
Chromosome analysis is indicated, for example, in the case of frontal lobe epilepsy and suspected ring chromosome 20 (mosaic). As several studies (Mefford et al, Ann Neurol 70(6), 974-985, 2011; Striano et al, Arch Neurol 69(3): 322-30, 2012) have shown that epilepsies can also occur with microdeletions and duplications, a microarray analysis may also be indicated, especially if developmental delay or other neuropsychiatric symptoms are present as an additional leading symptom.
References
Ishida et al. 2013, Nat Genet 45:552 / Dibbens et al. 2013, Nat Genet 45:546 / Hoppman-Chaney N et al. 2012, Clin Genet, 83:345 / Tavyev Asher YJ et al. 2012, Eur J Med Genet 55:299 / Striano P et al. 2012, Arch Neurol 69:322 / Noh GL et al. 2012, Eur J Med Genet 55: 281 / Jiang Y et al. 2012, Hum Genet 131:1217 / Weber YG et al. 2011, Z Epileptol 24: 100 / von Spiczak S et al. 2011, Z Epileptol 24:108 / Nicita F et al. 2011, Seizure 21:3 / Muhle H et al. 2011, Epilepsia 52:e194 / Mefford HC et al. 2011, Ann Neurol 70:974 / Kortüm F et al. 2011, J Med Genet 48:396 / Fountain-Capal JK et al. 2011, Ped Neurol 45: 319 / Becker F et al. 2011, Z Epileptol 24:93 / Rees M 2010, Seizure 19:680 / Ottmann R et al. 2010, Epilepsia 51:655 / Depienne C et al. 2010, Hum Mut 32:E1959 / de Kovel CGF et al. 2010, Brain 133:23 / Berg AT et al. 2010, Akt Neurol 37:120 / Deprez L et al. 2009, Neurology 72:273 / OMIM, Online Mendelian Inheritance In Man
