Identification of genetic variants in a pedigree associated with epilepsy by using whole exome sequencing and whole genome sequencing.

Epilepsy is a common heterogeneous group of neurological disorders including electroencephalographic and brain imaging. We used whole exome sequencing and whole genome sequencing to identify variants in a pedigree associated with epilepsy. Cranium CT scan showed that the lateral right parietal lobe was hyperdense, and there were no clear boundaries with brain tissue in affected cases. Using WES, one exclusive nonsynonymous mutant in gene TSC2 (Chr16:2138307; c.5240 T > G; p.Ile1747Ser) was involved in this disease. Further analysis showed that de novo variant in TSC2 was high conserved across different species. Moreover, the two affected sisters and their father had the same compound heterozygous variants in TSC2, while the father had no epilepsy but depigmentation. These variants demonstrated that variant in TSC2 may result in epilepsy with incomplete penetrance in humans, and the CNV and SV variants we identified probably be involved in this disease.

Brain morphological abnormalities in children with cyclin-dependent kinase-like 5 deficiency disorder.

BACKGROUND: To quantitatively evaluate the brain MRI morphological abnormalities in patients with cyclin-dependent kinase-like 5 deficiency disorder (CDD) on a group level and longitudinally. METHODS: We performed surface-based MRI analysis on high-resolution T1-weighted images on three CDD patients scanned at age of three years, and compared with 12 age- and gender-matched healthy controls. We further examined the longitudinal morphological changes in one patient with a follow-up of 5 years. RESULTS: CDD patients presented significant reductions in total intracranial volume, total gray matter (GM) volume and subcortical GM volume compared to controls. For subcortical regions, significant GM volume reductions were seen in the brain stem, bilateral thalamus, bilateral hippocampus, bilateral cerebellum and left amygdala. Although GM volume of cortical mantle did not show statistical differences overall, significant reduction was detected in bilateral parietal, left occipital and right temporal lobes. Cortical thickness exhibited significant decreases in bilateral occipital, parietal and temporal lobes, while surface area did not show any significant differences. Longitudinal follow-up in one patient revealed a monotonic downward trend of relative volume in the majority of brain regions. The relative surface area appeared to gain age-related growth, whereas the relative cortical thickness exhibited a striking progressive decline over time. CONCLUSIONS: Quantitative morphology analysis in children with CDD showed global volume loss in the cortex and more notably in the subcortical gray matter, with a progressive trend along with the disease course. Cortical thickness is a more sensitive measure to disclose cortical atrophy and disease progression than surface area.

Cortico-striato-thalamo-cerebellar networks of structural covariance underlying different epilepsy syndromes associated with generalized tonic-clonic seizures.

Generalized tonic-clonic seizures (GTCS) are the severest and most remarkable clinical expressions of human epilepsy. Cortical, subcortical, and cerebellar structures, organized with different network patterns, underlying the pathophysiological substrates of genetic associated epilepsy with GTCS (GE-GTCS) and focal epilepsy associated with focal to bilateral tonic-clonic seizure (FE-FBTS). Structural covariance analysis can delineate the features of epilepsy network related with long-term effects from seizure. Morphometric MRI data of 111 patients with GE-GTCS, 111 patients with FE-FBTS and 111 healthy controls were studied. Cortico-striato-thalao-cerebellar networks of structural covariance within the gray matter were constructed using a Winner-take-all strategy with five cortical parcellations. Comparisons of structural covariance networks were conducted using permutation tests, and module effects of disease duration on networks were conducted using GLM model. Both patient groups showed increased connectivity of structural covariance relative to controls, mainly within the striatum and thalamus, and mostly correlated with the frontal, motor, and somatosensory cortices. Connectivity changes increased as a function of epilepsy durations. FE-FBTS showed more intensive and extensive gray matter changes with volumetric loss and connectivity increment than GE-GTCS. Our findings implicated cortico-striato-thalamo-cerebellar network changes at a large temporal scale in GTCS, with FE-FBTS showing more severe network disruption. The study contributed novel imaging evidence for understanding the different epilepsy syndromes associated with generalized seizures.

The spectrum of neuroimaging findings in febrile infection-related epilepsy syndrome (FIRES): A literature review.

Febrile infection-related epilepsy syndrome (FIRES) is a rare severe epileptic syndrome occurring in previously healthy children and characterized by refractory status epilepticus (SE) following a febrile illness. Brain imaging findings in affected patients have been reported in few case series and some case reports. This article is a comprehensive review of the magnetic resonance imaging (MRI) characteristics in all reported patients with a diagnosis of FIRES, describing the findings in the acute and chronic phases of the disease, and discussing possible pathogenesis and radiologic differential diagnoses. Most of the patients had normal brain scans in the acute phase (61%) and about 25% of the patients reported in literature had abnormalities in the temporal lobes. Changes in the basal ganglia and rarely in thalami or brainstem have also been described, as well as diffuse cerebral edema in a minority of patients during the acute phase. The chronic phase of the disease was characterized by atrophic changes and evidence of mesiotemporal sclerosis. An understanding of these MRI abnormalities is necessary to support the diagnosis of FIRES and exclude mimics.

Memory in children with epilepsy: Utility of the WRAML-2 in generalized and focal epilepsy syndromes.

The material-specific model for memory impairment predicts that verbal memory deficits are seen with left temporal seizures, and visual memory deficits are seen with right temporal seizures (Henkin et al., 2005). In pediatric epilepsy, seizure pathology has not always yielded the expected material-specific memory profiles. This study used the Wide Range Assessment of Memory and Learning-Second Edition (WRAML-2) to assess memory functioning among pediatric patients with epilepsy. The WRAML-2 was administered to 180 youth with epilepsy during their neuropsychological evaluations. Memory and recognition scores correlated significantly with epilepsy severity variables. There were no significant differences in verbal and visual memory and recognition index scores among patients with generalized epilepsy or among those with lateralized or localized electroencephalography (EEG) patterns and lesions on imaging. However, clinically meaningful verbal versus visual discrepancy scores were significantly related to lateralized abnormalities on EEG and magnetic resonance imaging (MRI) results. Most patients with right hemisphere pathology showed the expected material-specific visual memory deficits, while fewer than 15% of the left hemisphere cases showed the expected verbal memory deficits. Over one-third of those with identified left-sided pathology showed clinically significant deficits in visual memory. Findings are incongruent with the material-specific memory model and reflect the fact that early developmental neurological insults can lead to functional reorganization/crowding effects in children with left hemisphere epilepsy. On exploratory analyses, there were no significant differences in discrepancy scores among participants with left, right, and bilateral languages on Wada and functional MRI (fMRI). However, those with right and bilateral language dominance were more likely to show discrepancies that were incongruent with the material-specific model.

Febrile infection-related epilepsy syndrome (FIRES): therapeutic complications, long-term neurological and neuroimaging follow-up.

PURPOSE: To understand the long-term neurological outcomes and chronological changes of brain MRIs in patients with febrile infection-related epilepsy syndrome (FIRES). METHODS: From December 2000 to May 2016, 29 patients diagnosed with FIRES were collected retrospectively. The demographic distribution, clinical manifestations, neuroimaging findings, and treatment methodology were described. Follow-up clinical outcomes and chronological evolution of neuroimaging findings were analyzed. RESULTS: The median age of disease onset was 8.9 years. The median duration of hospitalization was 87 days. During the period of hospitalization, more than 50% of patients exhibited complications such as skin rash, liver function impairment, and arrhythmia. Abnormal findings were found in 38% of neuroimaging studies in the initial study and in 87% of the follow-up brain MRI. Focal abnormal signal changes over the periventricular white matter suggested the more extensive lesions would be associated with a poorer clinical outcome. The median duration of follow-up was 5 years in 23 patients. In total, 87% of patients exhibited residual and/or refractory epilepsy. Regarding cognitive function, 26% of patients had normal intelligence quotient, 26% had learning disability and mild to moderate mental retardation, and 48% had severe mental retardation or vegetative status. The mortality rate at acute stage was 10%, and that at chronic stage was 13%. CONCLUSIONS: Liver function impairment, skin rash, and arrhythmia are frequently seen during hospitalization for FIRES at the acute stage of disease course. The higher grade of periventricular white matter lesions suggested poorer neurological outcomes. Studies on the pathomechanism of FIRES are crucially needed so that new treatment strategies for FIRES can be developed, which may improve long-term outcomes.

[Neuroimaging in epileptic encephalopathies in infants]. / Neuroimagen en las encefalopatias epilepticas del lactante.

Magnetic resonance plays a vital role in the aetiological diagnosis of epileptic encephalopathies, since it is capable of identifying specific aetiological patterns or patterns which are suggestive of different conditions. We review the main magnetic resonance findings that are observed in symptomatic epileptic encephalopathies.

TITLE: Neuroimagen en las encefalopatias epilepticas del lactante.La resonancia magnetica desempeña un papel crucial en el diagnostico etiologico de las encefalopatias epilepticas, al poder identificar patrones etiologicamente especificos o sugestivos de diferentes entidades. Se revisan los principales hallazgos por resonancia magnetica que se objetivan en las encefalopatias epilepticas sintomaticas.

[Infantile epileptic encephalopathies: what matters is genetics]. / Encefalopatias epilepticas del lactante: lo prioritario es el estudio genetico.

INTRODUCTION: Epileptic encephalopathies in infancy are defined as conditions where the sustained epileptic activity itself may contribute to the severe neurological and cognitive impairment. These epileptic encephalopathies include Ohtahara syndrome, early myoclonic epileptic encephalopathy, West syndrome, Dravet syndrome, and malignant migrating epilepsy in infancy. These syndromes result from identifiable primary causes, such as structural, neurodegenerative, metabolic, or genetic defects. AIM: To present and discuss current knowledge regarding genetic findings in epileptic encephalopathies in infancy, phenotype-genotype correlations in different forms of paediatric epileptic encephalopathies, and the impact of these new findings in clinical practice. DEVELOPMENT: Patients with unclear etiologies after performing a brain magnetic resonance imaging should be considered for a further workup, which should include an evaluation for genetic defects. Nowadays, more than 50 genes have been associated with epileptic encephalopathies in infancy. Targeted next-generation sequencing panels show a high diagnostic yield in patients with epileptic encephalopathies. CONCLUSIONS: Genetic knowledge about epileptic encephalopathies in infancy has revolutionized the diagnostic approach to these disorders, and an increasing number of gene mutations have been related to their pathogenesis. A more detailed classification of epileptic encephalopathies genotypes will improve the accuracy of genotype-phenotype correlation and genetic counseling. All these developments could yield therapeutic applications such as gene therapy or antiepileptic drugs 'tailored' to the specific genetic markers or targets.

TITLE: Encefalopatias epilepticas del lactante: lo prioritario es el estudio genetico.Introduccion. Las encefalopatias epilepticas del lactante constituyen un grupo de entidades donde la actividad epileptica mantenida contribuye por si misma al deterioro neurologico y cognitivo del paciente. Entre ellas se incluyen el sindrome de Ohtahara, la encefalopatia mioclonica precoz, el sindrome de West, el sindrome de Dravet y la epilepsia migratoria maligna del lactante. Estos sindromes se originan por etiologias variadas, incluyendo lesiones estructurales cerebrales, enfermedades metabolicas y heredodegenerativas, y alteraciones geneticas, entre otras. Objetivo. Presentar y discutir el conocimiento actual sobre los hallazgos geneticos en las encefalopatias epilepticas del lactante, el potencial correlato genotipo-fenotipo en las distintas formas de encefalopatias epilepticas y el impacto de estos nuevos hallazgos en la practica clinica. Desarrollo. En los lactantes con encefalopatias epilepticas, sin una etiologia definida tras realizar una resonancia magnetica cerebral, debe considerarse un abordaje etiologico que excluya patologias geneticas. En la actualidad, mas de 50 genes se han asociado con la etiologia de las encefalopatias epilepticas del lactante. Los paneles de multiples genes analizados por tecnicas de secuenciacion masiva son una herramienta util para el diagnostico genetico de estos pacientes. Conclusiones. El conocimiento sobre la genetica de las encefalopatias epilepticas del lactante ha revolucionado el abordaje diagnostico y cada vez se implican mas genes y distintos tipos de mutaciones en la patogenia de estas patologias. El desarrollo de clasificaciones especificas para las encefalopatias epilepticas geneticas puede contribuir a un mejor correlato genotipo-fenotipo, a orientar mejor el consejo genetico y a considerar terapias especificas.

[Epileptic syndromes in childhood associated with secondary generalized tonic-clonic seizures]. / Épilepticheskie sindromy v detskom vozraste, assotsiirovannye s vtorichno-generalizovannymi sudorozhnymi pristupami.

AIM: To study a group of patients with secondary generalized tonic-clonic seizures (SGTCS) in view of nosology, medical history, clinical, electroencephalographic and neuroimaging features. MATERIAL AND METHODS: The study included 471 patients, 244 (51.8%) men and 227 (48.2%) women. RESULTS: SGTCS were observed in many epileptic syndromes. The most frequent were symptomatic focal epilepsy (33.8%), cryptogenic focal epilepsy (23.8%), rolandic epilepsy (12.6%), FEBL-BEDC syndrome (12.3%). Other forms of epilepsy were less frequent. The onset of epilepsy ranged over a wide age range from the first month of life to 18 years. The average age of onset was 5.7±4.96 years. SGTCS as the only type of paroxysms were observed in 28.3% of cases. Two or more types of seizures were observed in 71.7% of patients, three or more types in 39.3%. Epileptiform activity on EEG during long VEM was detected in 91.3% of patients with SGTCS. In 37.2% of patients, benign epileptiform discharges of childhood were recorded. Treatment with antiepileptic drugs (AEP) led to complete remission in 57.1% of cases of epilepsy associated with SGTCS. A reduction of the frequency of seizures by 50% or more was found in 33.6% of patients treated with AEP. No effect was observed in 9.3% of patients. CONCLUSION: Significant differences in the prognosis and therapeutic approaches to specific epileptic syndromes associated with SGTCS necessitate the use of the entire spectrum of diagnostic measures, which should include careful history taking, clinical examination, video-EEG monitoring with the inclusion of sleep dynamics, MRI / CT brain, genetic testing.