Early-onset epileptic encephalopathies and the diagnostic approach to underlying causes

Hwang, Seung-Hyun; Kwon, Soonhak

doi:10.3345/kjp.2015.58.11.407

Cited by 21 publications

(23 citation statements)

References 59 publications

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“…EOEEs have three main features: refractory seizures, severe electroencephalography (EEG) abnormalities, and developmental delay (DD) or intellectual disability (ID) . EOEEs include some syndromes such as Ohtahara syndrome (OS), West syndrome (WS), early myoclonic encephalopathy, malignant migrating focal seizures of infancy (MMFSI), and Dravet syndrome (DS) as well as non‐specific epileptic encephalopathy . The etiologies of this disease are complex and diverse.…”

Section: List Of 17 Candidate Genesmentioning

confidence: 99%

Gene mutation analysis of 175 Chinese patients with early‐onset epileptic encephalopathy

Zhang

Zhao

et al. 2017

Clinical Genetics

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The aim of the study is to investigate the genetic characteristics and clinical features of a cohort of Chinese patients with early-onset epileptic encephalopathies (EOEEs). Targeted next-generation sequencing (NGS), focusing on 17 genes, was performed on 175 Chinese patients with EOEEs to screen gene mutations. The mutation rate was 32% (56/175). All mutations were de novo and heterozygous, including 41 novel and 15 reported mutations. Patients with cyclin-dependent kinase-like 5 (CDKL5) gene mutation accounted for the largest proportion, 13.1% (23/175). All patients with CDKL5 mutation presented severe psychomotor developmental delay and refractory seizures. The female patients presented obvious Rett-like features, which were not observed in male patients. Potassium channel, voltage-gated KQT-like subfamily Q, member 2(KCNQ2) gene mutations were detected in 13 patients. Patients with this mutation presented with early seizure onset within the first week after birth. Valproate (VPA), levetiracetam (LEV) and topiramate (TPM) were effective in most patients. Patients with specific gene mutations presented some unique clinical features, but not always. Many genes are involved in EOEEs. Targeted NGS showed a high diagnostic yield in patients with EOEEs. These findings provide useful insights for recommending treatment of gene-associated EOEEs using antiepileptic drugs.

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Section: List Of 17 Candidate Genesmentioning

confidence: 99%

Gene mutation analysis of 175 Chinese patients with early‐onset epileptic encephalopathy

Zhang

Zhao

et al. 2017

Clinical Genetics

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“…The inclusion criteria of sequencing are as follows: (1) insertion or deletion mutations, (2) mutations in coding amino acids or termination codons, (3) mutations in splicing sites, (4) non-synonymous mutations may destroy protein function predicted by PolyPhen-2 HVAR.…”

Section: Next Generation Sequencing and Copy Number Variation Studiesmentioning

confidence: 99%

Phenotypic Spectrum and Long-term Outcome in Children With Genetic Causes of Early-onset Epileptic Encephalopathy

Liu

Luo

et al. 2021

Preprint

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Background To explore the clinical phenotype and long-term outcome in children with genetic causes of early-onset epileptic encephalopathies. Methods The clinical data of 118 children between 2010 and 2020 was obtained and analyzed. The whole exome sequencing and copy number variation studies in family were used to find pathogenic mutations. The confirmed mutations were verified by Sanger sequencing. Results Among 118 patients, 39 patients were diagnosed with DS, 18 were WS, 3 were OS, 3 were EME, 2 were MMFSI, 1 was GLUT1 deficiency syndrome, 1 was Pyridoxine dependent epilepsy and 51 were non-symptomatic EOEEs. The initial EEG showed frequent multiple and multifocal sharp waves, spike waves, sharp slow waves or spike slow waves. In the later period, some transformed into infrequent discharging or normal EEG. 112 patients (112/118, 94.9%) showed normal brain MRI, and the remaining 6 had widened extracerebral space. In the later stage, 115 patients were re-examined with brain MRI 1 to 3 times, the widened gap became normal, only 2 had mild brain atrophy. After treatment, 42 patients (42/118, 35.6%) had seizure control. In EOEE-BS, 6 patients were found KCNQ2 mutations and the remaining mutations were SCN2A (n=2), STXBP1 (n=1). After treatment, only 2 patients had seizure control, 6 had uncontrolled seizures and 1 died. 7 patients with dyskinesia were found. 1 patient starting with a febrile convulsion was caused by HNRNPU mutation. SCN1A mutations were detected in 38 patients (38/118, 32.2%), representing the largest proportion. The second common mutations were KCNQ2 mutations in 9 patients. The third one was CDKL5 mutations in 8 patients. Genes associated with ionic channels represented the largest proportion (66/118, 55.9%), sodium channel potassium channel and calcium channel respectively. In WS, we detected SCN3A, SCN2A, SCN8A, CACNA1H, DEPDC5, MECP2, DYNC1H1, CDKL5, ALG11, CCDC88C, GABAA1, IL1RAPL1, RNASEH2B, SLC19A3, STXBP1, QARS, COL4A2 mutations. In addition to common gene mutations, we reported rare possible pathogenic genes: CCDC88C, IL1RAPL1, RNASEH2B and COL4A2 in WS. In non-syndromic genetic causes of EOEEs, we detected rare possible pathogenic genes: SETBP1, DPYD, CSNK2B and H3F3A. As for genetic modes, denovo heterozygous mutations account for the largest proportion (104/118, 88.1%). 3 patients with SMC1A mutations response to KD add-on therapy. VPA added treatment showed good effects on KCNB1 and PACS2 encephalopathy. LEV showed good effects on STXBP1, and OXC showed good effects on SCN8A encephalopathy. Conclusion The clinical manifestations of EOEE are variable, including dyskinesia. EOEE-BS usually response poorly to AEDS therapy. Although some patients achieve seizure-free, there is no remarkable improvement in their development. EOEEs starting with a febrile convulsion may be a special phenotype of HNRNPU related neurodevelopmental syndrome, similar to DS. We report rare possible pathogenic genes: CCDC88C, IL1RAPL1, RNASEH2B, COL4A2 in WS and detect rare possible pathogenic genes: SETBP1, DPYD, CSNK2B and H3F3A in non-syndromic genetic causes of EOEEs. Although genetic causes of EOEEs response poorly to AEDS treatment, we find that some gene mutation related EOEEs receive good effects on specific AEDS.

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“…The most frequent genetic abnormalities linked with OS are aristaless-related homeobox (ARX) gene mutations at Xp22.13, cyclin-dependent kinase-like 5 (CLDK5) (STK9) gene at Xp22, solute carrier family 25 [mt carrier, glutamate carrier-1/GC-1] member 22 (SLC25A22) gene at 11p15.5, STXBP1 (MUNC18-1) gene microdeletion at 9 q33.3-q34.11, KCNQ2 gene mutations, SCN2A gene mutations, and GABRA1 gene mutations [14].…”

Section: Etiologymentioning

confidence: 99%

“…Several of the genes may manifest as phenotypes that overlap not only with OS and EME but also with other EEs such as West syndrome [14].…”

Section: Etiologymentioning

confidence: 99%

Epileptic Encephalopathies in Infants and Children

Fernández-Concepción¹,

López-Jiménez²

2019

Epilepsy - Advances in Diagnosis and Therapy

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Epileptic encephalopathies represent a group of devastating epileptic disorders that appear early in life. They are characterized by pharmacoresistant generalized or focal seizures, persistent severe EEG abnormalities, and cognitive dysfunction or decline. The ictal and interictal epileptic discharges are age-specific and either are the main cause or contribute to cognitive deterioration in the idiopathic or symptomatic group, respectively. Despite choosing the most appropriate antiepileptic drugs for the seizure type and syndrome, the results are often disappointing, and polytherapy and/ or alternative therapy becomes unavoidable; in those cases, consideration should be given to the quality of life of the child and carers. In this chapter, we will discuss the clinical and electroencephalographic characteristics and evolution and management of age-related epileptic encephalopathies, recognized by the International League Against Epilepsy, as follows: early infantile epileptic encephalopathy (Ohtahara syndrome), early myoclonic encephalopathy, epilepsy of infancy with migrating focal seizures, infantile spasms (West syndrome), severe myoclonic epilepsy in infancy (Dravet syndrome), myoclonic-atonic epilepsy (Doose syndrome), Lennox-Gastaut syndrome, epileptic encephalopathy with continuous spike-and-wave during sleep, and Landau-Kleffner syndrome. Their clinical features, prognosis, etiologies, and treatment are presented and updated.

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Early-onset epileptic encephalopathies and the diagnostic approach to underlying causes

Cited by 21 publications

References 59 publications

Gene mutation analysis of 175 Chinese patients with early‐onset epileptic encephalopathy

Gene mutation analysis of 175 Chinese patients with early‐onset epileptic encephalopathy

Phenotypic Spectrum and Long-term Outcome in Children With Genetic Causes of Early-onset Epileptic Encephalopathy

Epileptic Encephalopathies in Infants and Children

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