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Recent Developments in the Genetics of Childhood Epileptic Encephalopathies: Impact in Clinical Practice

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Recent Developments in the Genetics of Childhood Epileptic Encephalopathies: Impact in Clinical Practice DOI: 10.1590/0004-282X20150122 VIEW AND REVIEW Recent developments in the genetics of childhood epileptic encephalopathies: impact in clinical practice Desenvolvimentos recentes na genética das encefalopatias epilépticas da infância: impacto na prática clínica Marina C. Gonsales1, Maria Augusta Montenegro2, Camila V. Soler1, Ana Carolina Coan,2, Marilisa M. Guerreiro2, Iscia Lopes-Cendes1 ABSTRacT Recent advances in molecular genetics led to the discovery of several genes for childhood epileptic encephalopathies (CEEs). As the knowledge about the genes associated with this group of disorders develops, it becomes evident that CEEs present a number of specific genetic characteristics, which will influence the use of molecular testing for clinical purposes. Among these, there are the presence of marked genetic heterogeneity and the high frequency of de novo mutations. Therefore, the main objectives of this review paper are to present and discuss current knowledge regarding i) new genetic findings in CEEs, ii) phenotype-genotype correlations in different forms of CEEs; and, most importantly, iii) the impact of these new findings in clinical practice. Accompanying this text we have included a comprehensive table, containing the list of genes currently known to be involved in the etiology of CEEs. Keywords: Dravet syndrome, Ohtahara syndrome, West syndrome, Lennox-Gastaut syndrome, Doose syndrome, Landau-Kleffner syndrome. RESUMO Os avanços recentes em genética molecular permitiram a descoberta de vários genes para encefalopatias epilépticas da infância (EEIs). À medida que o conhecimento sobre os genes associados a este grupo de doenças se desenvolve, torna-se evidente que as EEIs apresentam uma série de características genéticas específicas, o que influencia o uso do teste molecular para fins clínicos. Entre as EEIs, há a presença de acentuada heterogeneidade genética e alta frequência de mutações de novo. Assim, os principais objetivos deste trabalho de revisão são apresentar e discutir o conhecimento atual a respeito de i) novas descobertas em genética molecular das EEIs, ii) correlações fenótipo-genótipo nas diferentes formas de EEIs; e, mais importante, iii) o impacto desses novos achados genéticos na prática clínica. Acompanhando o texto, incluímos uma tabela contendo a lista de genes conhecidos atualmente como envolvidos na etiologia da EEIs. Palavras-chave: síndrome de Dravet, síndrome de Ohtahara, síndrome de West, síndrome de Lennox-Gastaut, síndrome de Doose, síndrome de Landau-Kleffner. The encephalopathic effects of epileptic activity may oc- Although the damaging effect of seizures can potentially hap- cur in association with any form of epilepsy; however, it is pen in any form of epilepsy, in some syndromes this impair- more often present in a number of syndromes called child- ment is virtually always present. According to current classi- hood epileptic encephalopathies (CEEs). CEEs are conditions fication1, the following syndromes are considered CEEs: early in which “the epileptic activity itself may contribute to severe myoclonic encephalopathy (EME), Ohtahara syndrome (OS), cognitive and behavioral impairment above and beyond what epilepsy of infancy with migrating focal seizures (EIMFS), might be expected from the underlying pathology alone (e.g., West syndrome (WS), Dravet syndrome, Doose syndrome or cortical malformation), and these can worsen over time”1. epilepsy with myoclonic atonic (previously astatic) seizures, 1Universidade de Campinas, Instituto Brasileiro de Neurociências e Neurotecnologia, Faculdade de Ciências Médicas, Departamento de Genética Médica, Campinas SP, Brazil; 2Universidade de Campinas, Instituto Brasileiro de Neurociências e Neurotecnologia, Faculdade de Ciências Médicas, Departamento de Neurologia, Campinas SP, Brazil. Correspondence: Iscia Lopes-Cendes; Rua Tessalia Vieira de Camargo, 126; Cidade Universitária Zeferino Vaz / UNICAMP; 13083-887 Campinas SP, Brasil; E-mail: [email protected] Conflict of interest: There is no conflict of interest to declare. Support: This work was supported by research grants from FAPESP and CNPq. MCG is supported by a fellowship from FAPESP and CVS is supported by a studentship from CNPq. Received 29 May 2015; Received in final form 01 July 2015; Accepted 20 July 2015. 1 Lennox-Gastaut syndrome (LGS), epileptic encephalopathy atypical absences, generalized tonic clonic and focal), and EEG with continuous spike-and-wave during sleep (CSWS), and during wakefulness showing diffuse slow spike-and-waves Landau-Kleffner syndrome (LKS). As widely recognized, (<2.5Hz). During sleep, EEG shows bursts of generalized fast each one of these different clinical entities have specific char- spikes around 10 Hz4. Although LGS can evolve from WS, it acteristics, including mainly clinical and EEG features, which may occur in a previously epilepsy free child. Both WS and make it possible to clinically recognize them; however, recent LGS can be associated with structural lesions such as mal- developments in the field of molecular genetics are helping formations of cortical development, vascular lesions, meta- to determine that there are many intermediary phenotypes, bolic disorders, etc. However, several patients present with a which can represent a great diagnostic challenge to clini- normal MRI. Therefore, determining the etiology of CEEs in cians. Patients presenting these transitional or less charac- these patients represents an additional challenge. teristic phenotypes are probably those who will benefit most Doose syndrome, or epilepsy with myoclonic atonic (pre- of the recently available genetic diagnostic tools, which will viously astatic) seizures, is characterized by multiple sei- help determining diagnosis and establishing an etiology. zure types such as atypical absence, atonic, tonic and myo- However, even for patients with a clinically well-defined syn- clonic astatic seizures. Its onset is between 7 months and drome within the group of CEEs a positive genetic test can 6 years-old5, and the prognosis is variable. Disturbances in define etiology. Therefore, the main objective of this review cognitive and psychomotor skills are often present. The EEG is to present and discuss current knowledge regarding i) new remains the best diagnostic tool available. molecular genetic findings in this group of disorders; ii) the Dravet syndrome was described in 1978 under the name complex phenotype-genotype correlations observed in the of severe myoclonic epilepsy of infancy6. It is characterized CEEs; and, most importantly, iii) the impact of these new ge- by febrile and afebrile generalized and unilateral, clonic or netic findings in clinical practice. tonic clonic, seizures, which occur in the first year of life in an otherwise normal infant. These can be later associat- ed with myoclonus, atypical absences, and partial seizures, MOST COMMON CEES and high sensitivity even to low-degree fever is observed6,7. Between the first and fourth years of life, some degree of cog- Early myoclonic encephalopathy (EME) is a neonatal epi- nitive impairment and behavior abnormality is often present. lepsy syndrome characterized by onset of myoclonic seizures Seizures are usually refractory to antiepileptic drug treat- usually within the first month of life and abnormal neurologi- ment. Photosensitivity may be present. However, photosensi- cal signs at birth or at the moment of seizure onset2. The EEG tivity can be difficult to evaluate because it may not be pres- presents with suppression-burst pattern with short paroxys- ent during the whole course of the disease6. mal bursts and longer periods of suppression, enhanced dur- Epileptic encephalopathy with continuous spike-and-wave ing sleep2. The syndrome has a poor prognosis with progres- during sleep (CSWS) is characterized by a typical EEG find- sive deterioration and early death. ing of continuous spike-and-wave discharges (usually dif- Ohtahara syndrome (OS), also called early infantile epilep- fuse, but sometimes focal) occurring in at least 85% of slow tic encephalopathy, is an age-dependent epileptic encephalop- sleep in children with focal or, eventually, generalized sei- athy characterized by tonic seizures with onset at the neonatal zures (electrical status epilepticus of sleep, ESES). Seizure period and EEG showing suppression-burst pattern with lon- onset usually occurs between 2 and 12 years and there is a ger periods of bursts and shorter periods of suppression2. The marked neurological deterioration in cognitive, behavioral prognosis is poor, with significant neurological impairment or and/or motor domains8. The treatment must aim the disap- death. Children with OS might evolve to West syndrome2. pearance of the ESES, which is the mechanism responsible Epilepsy of infancy with migrating focal seizures (EIMFS) for the encephalopathy. is a rare epileptic syndrome characterized by onset of multifo- Landau-Kleffner syndrome (LKS) or syndrome of acquired cal focal seizures within the first 6 months of life and an ictal aphasia with convulsive disorder in children is an epileptic en- EEG demonstrating seizures independently arising and mov- cephalopathy that occurs in previously normal children with ing sequentially from both hemispheres. The syndrome pro- normally developed age-appropriated language9. It is charac- gresses as intractable seizures and further psychomotor delay3. terized by seizures and acquired aphasia, typically verbal au- West syndrome (WS) is characterized by developmental ditory agnosia, with onset
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