Form Of Epileptic Encephalopathy Research Articles

Пренатальні, перинатальні та неонатальні фактори ризику народження дітей з епілептичними енцефалопатіями

The negative impact of perinatal factors on the brain can play a significant role in the etiopathogenesis of epileptic seizures in young children and the development of epileptic encephalopathies (EE). Purpose - to study the characteristics of the course of the prenatal and neonatal periods in young children with EE for the further formation of risk groups of children who need active monitoring. Materials and methods. An analysis of prenatal and neonatal features of anamnesis of 157 children with EE and their mothers was carried out. The children were divided into 3 groups: the Group I - children with EE who had the debut of epileptic seizures before the age of 1 year (n=75); the Group II - children with EE who had the debut of epileptic seizures after the age of 1 year (n=44); the Group III - children with epileptiform and developmental encephalopathies (EDE) (n=38). Results. The course of pregnancy in mothers of children with EDE is characterized by a high frequency of early gestosis, the threat of abortion in the second half of pregnancy and polyhydramnios (28.9%, 31.6%, 23.7%, respectively). Some (31.6%) of children with EDE were born prematurely, 21.1% by emergency caesarean section. Childbirth in mothers of children with EDE was characterised by a pathological course (44.7%), weakness of labor activity and prolonged dehydration (36.8% and 28.9%, respectively), and the birth of a child with distress (21.1%). The course of the neonatal period in children with EDE was characterized by a higher frequency of hypoxic-ischemic encephalopathy (23.7%) than in children with other forms of EE. In children of the Group I, syndromes of motor disorders (20.0%) and muscle hypotonia (17.3%) were more often observed. Conclusions. Aggravating factors of obstetric-gynecological and somatic anamnesis in women, and the course of prenatal and neonatal periods of life, which can act as a basis for the formation of EE and EDE in children, have been established. Among them are preeclampsia, placental pathology, changes in the amount of amniotic fluid during pregnancy, pathological childbirth, central nervous system depression syndrome and convulsive syndrome in infants. The obtained data will contribute to the formation of high-risk groups of children who need active monitoring. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Reversal of cell, circuit and seizure phenotypes in a mouse model of DNM1 epileptic encephalopathy

Dynamin-1 is a large GTPase with an obligatory role in synaptic vesicle endocytosis at mammalian nerve terminals. Heterozygous missense mutations in the dynamin-1 gene (DNM1) cause a novel form of epileptic encephalopathy, with pathogenic mutations clustering within regions required for its essential GTPase activity. We reveal the most prevalent pathogenic DNM1 mutation, R237W, disrupts dynamin-1 enzyme activity and endocytosis when overexpressed in central neurons. To determine how this mutation impacted cell, circuit and behavioural function, we generated a mouse carrying the R237W mutation. Neurons from heterozygous mice display dysfunctional endocytosis, in addition to altered excitatory neurotransmission and seizure-like phenotypes. Importantly, these phenotypes are corrected at the cell, circuit and in vivo level by the drug, BMS-204352, which accelerates endocytosis. Here, we demonstrate a credible link between dysfunctional endocytosis and epileptic encephalopathy, and importantly reveal that synaptic vesicle recycling may be a viable therapeutic target for monogenic intractable epilepsies.

Establishment of an induced pluripotent stem cell line (ZJSHi001-A) from a patient with epileptic encephalopathy carrying KCNB1 Glu330Asp mutation.

Early infantile epileptic encephalopathy 26 (EE26) is a form of epileptic encephalopathy, a heterogeneous group of severe childhood-onset epilepsies characterized by refractory seizures, neurodevelopmental impairment, and poor prognosis. A recent study has shown that the KCNB1 gene mutation is associated with EE26; yet, the exact mechanism remains unclear. In this study, we produced an induced pluripotent stem cell line (iPSC) with a heterozygous variant of the KCNB1 gene (c.990G>T, p.Glu330Asp). Induced iPSCs were generated from peripheral blood mononuclear cells (PBMCs) obtained from a female child aged 6 with KCNB1 gene c. 990G>T and p.Glu330Asp heterozygous mutation.

Genetically encoded multimode reporter of adaptor complex 3 traffic in budding yeast.

AP-3 (adaptor complex 3) mediates traffic from the late Golgi or early endosomes to late endosomal compartments. In mammals, mutations in AP-3 cause Hermansky-Pudlak syndrome type 2, cyclic neutropenias, and a form of epileptic encephalopathy. In budding yeast, AP-3 carries cargo directly from the trans-Golgi to the lysosomal vacuole. Despite the pathway's importance and its discovery two decades ago, rapid screens and selections for AP-3 mutants have not been available. We now report GNSI, a synthetic, genetically encoded reporter that allows rapid plate-based assessment of AP-3 functional deficiency, using either chromogenic or growth phenotype readouts. This system identifies defects in both the formation and consumption of AP-3 carrier vesicles and is adaptable to high-throughput screening or selection in both plate array and liquid batch culture formats. Episomal and integrating plasmids encoding GNSI have been submitted to the Addgene repository.

A case-control collapsing analysis identifies epilepsy genes implicated in trio sequencing studies focused on de novo mutations.

Trio exome sequencing has been successful in identifying genes with de novo mutations (DNMs) causing epileptic encephalopathy (EE) and other neurodevelopmental disorders. Here, we evaluate how well a case-control collapsing analysis recovers genes causing dominant forms of EE originally implicated by DNM analysis. We performed a genome-wide search for an enrichment of "qualifying variants" in protein-coding genes in 488 unrelated cases compared to 12,151 unrelated controls. These "qualifying variants" were selected to be extremely rare variants predicted to functionally impact the protein to enrich for likely pathogenic variants. Despite modest sample size, three known EE genes (KCNT1, SCN2A, and STXBP1) achieved genome-wide significance (p<2.68×10−6). In addition, six of the 10 most significantly associated genes are known EE genes, and the majority of the known EE genes (17 out of 25) originally implicated in trio sequencing are nominally significant (p<0.05), a proportion significantly higher than the expected (Fisher’s exact p = 2.33×10−17). Our results indicate that a case-control collapsing analysis can identify several of the EE genes originally implicated in trio sequencing studies, and clearly show that additional genes would be implicated with larger sample sizes. The case-control analysis not only makes discovery easier and more economical in early onset disorders, particularly when large cohorts are available, but also supports the use of this approach to identify genes in diseases that present later in life when parents are not readily available.

Moyamoya in a Patient with FIRES: A First Case Report

ABSTRACTFebrile infection-related epilepsy syndrome (FIRES) is a form of epileptic encephalopathy with severe refractory epilepsy that presents in previously healthy, school-aged children after significant febrile illness with concomitant rise in body temperature. Suspected causes include genetic or acquired channelopathies, as well as mitochondrial disturbances. In FIRES, the EEG shows diffuse slowing, generalized, and/or multifocal discharges. Seizures are present and resistant to treatment. Moyamoya angiopathy (MMA) is characterized by progressive stenosis of cerebral arteries and subsequent development of a network of collateral circulation that is prone to rupture. We present here a case of a 6-year-old patient with a postfebrile illness, acute and explosive bilateral independent seizure onset that was most consistent with FIRES, but also with imaging evidence of right-sided-only MMA. Our patient demonstrated two diseases not described together previously in the literature. It is unknown whether this patient’s MMA is related to FIRES. In spite of successful corrective surgery (encephaloduroarteriosynangiosis), the patient continues to suffer from intractable seizures (mostly on the right) and apparent mild encephalopathy. The impact of our interventions (surgery, antiepileptic medication) is unclear. In this article, we describe a case of MMA and FIRES, and the history, physical, laboratory, imaging, and developmental elements of the 6-year-old patient with previously normal development.

Diagnostic odyssey in severe neurodevelopmental disorders: toward clinical whole-exome sequencing as a first-line diagnostic test.

The current standard of care for diagnosis of severe intellectual disability (ID) and epileptic encephalopathy (EE) results in a diagnostic yield of ∼50%. Affected individuals nonetheless undergo multiple clinical evaluations and low-yield laboratory tests often referred to as a 'diagnostic odyssey'. This study was aimed at assessing the utility of clinical whole-exome sequencing (WES) in individuals with undiagnosed and severe forms of ID and EE, and the feasibility of its implementation in routine practice by a small regional genetic center. We performed WES in a cohort of 43 unrelated individuals with undiagnosed ID and/or EE. All individuals had undergone multiple clinical evaluations and diagnostic tests over the years, with no definitive diagnosis. Sequencing data analysis and interpretation were carried out at the local molecular genetics laboratory. The diagnostic rate of WES reached 32.5% (14 out of 43 individuals). Genetic diagnosis had a direct impact on clinical management in four families, including a prenatal diagnostic test in one family. Our data emphasize the clinical utility and feasibility of WES in individuals with undiagnosed forms of ID and EE and highlight the necessity of close collaborations between ordering physicians, molecular geneticists, bioinformaticians and researchers for accurate data interpretation.

A febrile epileptic status in a child: FIRES syndrome. A case report

The article describes a clinical case of severe childhood epileptic syndrome, FIRES (DESC) syndrome, which is a form of epileptic encephalopathy in school-age children caused by hyperthermia. The emergence of this severe childhood condition leads to involvement of all diagnostic and human resources available at a pediatric critical care clinic to identify and treat this form of epileptic paroxysm. The described clinical case also had a severe course with a prolonged epileptic status, which was resistant to antiepileptic pharmacotherapy, and hyperthermia. The presented case is a modest contribution to the treasury of information about this syndrome in our country, with the aim to increase the doctors’ awareness of the problem.

Clinical and electroencephalographic characteristics of some forms of epileptic encephalopathies in infants: The data of the authors' follow-up observations

Objective: to study clinical symptoms and brain activity in new forms of infantile epilepsy, such as malignant migrating partial seizures in infancy (MMPSI) and Markand-Blume-Ohtahara syndrome (MBOS) and to elaborate their differential diagnostic criteria for the timely choice of treatment policy and for the prediction of the disease. Patients and methods. Thirty-eight children aged 1.5 months to 3 years with MMPSI and MBOS were examined. Their medical history and neurological examination data, electroencephalographic and neuroimaging characteristics, and the efficiency of chosen anticonvulsant therapy were investigated. Results and discussion. The investigators revealed the following characteristics of these forms: the causes of these syndromes were highly diverse and unspecific; the neurological status was characterized by a variety of symptoms with an obvious delay in psycho-prespeech development concurrent with a high rate of partial focal (in MMPSI) and generalized (in MBOS) status epilepticus; The EEC characteristic sign was MISF and «lafa» patterns in the children with MBOS and continuous migrating partial ictal status epilepticus patterns in those with MMPSI. These forms of epileptic encephalopathies are extremely drug-resistant and characterized by a high risk for a fatal outcome.

Genetics and treatment of early infantile epileptic encephalopathies

Epileptic encephalopathies (EE) are the group of progressive conditions with various etiologies that can produce neurocognitive deficit both per se and due to constant epileptiform discharges. Epileptic encephalopathies constitute about 15% of epilepsy in childhood and 40% of all seizures occurring in the first 3 years of life. Ten syndrome forms of EE are identified. Genetic factors contribute to 70-80% of all epileptic diseases and approximately 40% of idiopathic epilepsies have a monogenic mode of inheritance. Thirty-five genes of EE have been identified and the search is still continuing. The marked genetic heterogeneity of early EE, including 16 with autosomal-dominant-, 13 with autosomal-recessive-, 4 with X-linked recessive- and 2 with X-linked autosomal inheritance, was shown. The article describes differentiated approaches to the treatment of certain EE syndromes. Recent publications record the effectiveness of targeted therapy for certain forms of monogenic early EE (stiripentol in SCN1A mutations, diphenine in SCN8A mutations, levetiracetam in STXBP1 mutations). These results indicate the necessity for accurate diagnosis of genetic variants in early infantile EE for preventive actions in burdened families and for increasing the effectiveness of treatment.

Clinical and EEG profile in Dravet and Doose syndromes

We studied 14 patients with severe myoclonic epilepsy of infancy (SMEI), mean age ± SD 8.5 ± 4.14 yr, 10 girls, and 13 patients with myoclonic astatic epilepsy (MAE), mean age ± SD 11.8 ± 5.19 yr, six girls. All patients underwent EEGs, cranial magnetic resonance imaging (MRI) and the Vineland scale for assessment of adaptive behavior in areas related to communication, activities of daily living, socialization, and motor skills. Our study revealed abnormalities in the neurological examination (ataxia, mild pyramidal tract abnormalities, hyperactivity, autism spectrum disorder) in all 14 patients with SMEI and 4 of the 8 patients with MAE. EEGs showed background slowing, and focal and generalized epileptiform activity in 10 patients with SMEI. In patients with MAE EEGs showed monomorphic centroparietal theta rhythm in nine patients, and generalized epileptiform activity in all patients. Deterioration of adaptive behavior occurred in all the patients with SMEI and in eight patients with MAE. SMEI and MAE showed clinical and EEG findings according to those previously described. Nevertheless, severe epileptic encephalopathy was detected in patients with SMEI while patients with MAE presented with a milder form of epileptic encephalopathy. The outcome was good in approximately one third of the patients with MAE.

Evolution of Ohtahara Syndrome to Continuous Spikes and Waves during Slow Sleep in an Infant

ABSTRACT.Encephalopathy with electrical status epilepticus in sleep (ESES) is defined as an age-related and self-limited electroclinical syndrome whose etiology is unknown and characterized by continuous spikes and waves during slow sleep (CSWS). Typical CSWS starts at an age of 4 to 5 years and ends by an average of 11 years. We report on an unexpected finding of CSWS in an 18-month-old male whose previous EEC at age 45 days was grossly abnormal with the presence of a burst suppression pattern during wakefulness and sleep. The patient had clinical seizures beginning day 1 of life leading to the suspicion of Ohtahara syndrome (the earliest form of epileptic encephalopathy). Patients with ESES usually have normal EEGs and functional development prior to the onset of CSWS pattern. To our knowledge, this presentation of a neonate with a history of neonatal seizures and developmental delay with an evolution to CSWS has not been described. A sleep record is strongly advised in children with epilepsy (despite the recording of awake EEG abnormalities), especially in patients with behavior or cognitive regression, to rule out the presence of CSWS.

Dravet Syndrome as Adult Form of Epileptic Encephalopathy

Researchers at the National Hospital, Queen Square, Great Ormond Street Hospital, and other centers in the UK and Melbourne, Australia identified a series of 22 adult patients (median age 39 years; range 20-66), including 3 post-mortem cases with Dravet syndrome.