Early-onset Epilepsy Research Articles

TBC1D24 regulates axonal outgrowth and membrane trafficking at the growth cone in rodent and human neurons.

Mutations in TBC1D24 are described in patients with a spectrum of neurological diseases, including mild and severe epilepsies and complex syndromic phenotypes such as Deafness, Onycodystrophy, Osteodystrophy, Mental Retardation and Seizure (DOORS) syndrome. The product of TBC1D24 is a multifunctional protein involved in neuronal development, regulation of synaptic vesicle trafficking, and protection from oxidative stress. Although pathogenic mutations in TBC1D24 span the entire coding sequence, no clear genotype/phenotype correlations have emerged. However most patients bearing predicted loss of function mutations exhibit a severe neurodevelopmental disorder. Aim of the study is to investigate the impact of TBC1D24 knockdown during the first stages of neuronal differentiation when axonal specification and outgrowth take place. In rat cortical primary neurons silenced for TBC1D24, we found defects in axonal specification, the maturation of axonal initial segment and action potential firing. The axonal phenotype was accompanied by an impairment of endocytosis at the growth cone and an altered activation of the TBC1D24 molecular partner ADP ribosylation factor 6. Accordingly, acute knockdown of TBC1D24 in cerebrocortical neurons in vivo analogously impairs callosal projections. The axonal defect was also investigated in human induced pluripotent stem cell-derived neurons from patients carrying TBC1D24 mutations. Reprogrammed neurons from a patient with severe developmental encephalopathy show significant axon formation defect that were absent from reprogrammed neurons of a patient with mild early onset epilepsy. Our data reveal that alterations of membrane trafficking at the growth cone induced by TBC1D24 loss of function cause axonal and excitability defects. The axonal phenotype correlates with the disease severity and highlight an important role for TBC1D24 in connectivity during brain development.

Psychoeducational implications of West Syndrome (infantile spasm) for primary school children

ABSTRACTWest Syndrome is a severe, early-onset epilepsy syndrome, with significant implications for subsequent neurological and cognitive development. While most children with a prior diagnosis of West Syndrome initially follow a normal developmental trajectory, there is evidence of subsequent emergence of clusters of difficulties, including autism features, behavioural problems and specific learning difficulties. A multiple case study approach was adopted to investigate the cognitive, academic, adaptive and behavioural functioning of five children, aged 8−13, with a prior diagnosis of West Syndrome, who were attending mainstream schools. A striking similarity across psychological profiles was observed. Despite generally functioning within the low average or average range, participants presented with delays in aspects of literacy, numeracy, and adaptive and behavioural functioning. The findings of this study indicate long-term neurological sequelae of a previous diagnosis of West Syndrome which need to be considered by educational psychologists when supporting such children in the education system.

A new cause of developmental and epileptic encephalopathy with continuous spike-and-wave during sleep: CDKL5 disorder

ABSTRACTThe CDKL5 disorder is characterized by early onset epilepsy, stereotypical hand movement, absent speech and severe hypotonia. Herein, we report epileptic encephalopathy with continuous spike-and-wave during sleep (CSWS) in apatient with CDKL5 disorder. She admitted with complaints of frequently recurring generalized tonic and myoclonic seizures. The diagnoses were confirmed by de novo CDKL5 mutation, c.197_198delCT (p.L67QfsX23). Interictal EEG revealed generalized spike and slow-wave activity, occurring intermittently in wakefulness but present for at least 85% of non-REM sleep, consistent with the diagnosis of CSWS. To our knowledge, this is the first report of CSWS associated with CDKL5 disorder.

Neurobehavioral problems in children with early-onset epilepsy: A population-based study

PurposeNeurobehavioral problems (i.e., cognitive impairment/behavior problems) are a major challenge in childhood epilepsy. Yet there are limited data in children with early-onset epilepsy (CWEOE; onset ≤4 years), the period in which the incidence of childhood epilepsy is highest. This study aimed to determine the prevalence, spectrum, and risk factors for neurobehavioral problems CWEOE. MethodsThis prospective, population-based, case-controlled study identified children with newly diagnosed early-onset epilepsy in South East Scotland using active multisource capture–recapture surveillance (May 2013 – June 2015). The CWEOE and controls completed an age-appropriate neurobehavioral assessment battery across seven domains: general cognitive ability (GCA), adaptive behavior, externalizing, internalizing, executive functioning, social functioning, and Autism Spectrum Disorder (ASD) risk. ResultsFifty-nine CWEOE were identified with an ascertainment of 98% (95% confidence interval [CI] 94, 103). Forty-six (78% [95% CI 65.9, 86.6]) CWEOE (27 male, median age 25.5, range 1–59, months) and 37 controls (18 male, median age 31.5, range 3–59, months) consented for study entry. The CWEOE were similar to controls in gender, age, prematurity, and family history of psychopathology, but not socioeconomic status (Fisher's exact test [FET] < .001). Neurobehavioral assessments were carried out a median of 2.97 (Interquartile range [IQR] 1.51–4.95) months post epilepsy diagnosis.More CWEOE (63% [95% CI 48.6, 75.5]) had neurobehavioral problems compared with controls (27% [95% CI 15.4, 43.0]); p < 0.01. This observation was independent of socioeconomic status. Multidimensional problems were prevalent in CWEOE with 43% having two or more different domain-level problems; GCA impairment, adaptive behavior, internalizing, social functioning, and ASD risk were particularly marked. Risk factors varied by domain. DiscussionThis novel study using comprehensive psychometric assessments found that neurobehavioral problems in CWEOE were detectable, common, and multidimensional. The degree of cooccurrence implies that problems are the norm, and multidimensional screening should be considered at epilepsy onset. The findings could aid policy development on health and educational provision in CWEOE.

Don't Fear the Reefer-Evidence Mounts for Plant-Based Cannabidiol as Treatment for Epilepsy.

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Biallelic VARS variants cause developmental encephalopathy with microcephaly that is recapitulated in vars knockout zebrafish

Aminoacyl tRNA synthetases (ARSs) link specific amino acids with their cognate transfer RNAs in a critical early step of protein translation. Mutations in ARSs have emerged as a cause of recessive, often complex neurological disease traits. Here we report an allelic series consisting of seven novel and two previously reported biallelic variants in valyl-tRNA synthetase (VARS) in ten patients with a developmental encephalopathy with microcephaly, often associated with early-onset epilepsy. In silico, in vitro, and yeast complementation assays demonstrate that the underlying pathomechanism of these mutations is most likely a loss of protein function. Zebrafish modeling accurately recapitulated some of the key neurological disease traits. These results provide both genetic and biological insights into neurodevelopmental disease and pave the way for further in-depth research on ARS related recessive disorders and precision therapies.

Genetic diagnosis of neonatal-onset seizures

Many seizures in neonates are due to early-onset epilepsy, which is often difficult to diagnose, especially to explore the causes. Recently, the development of next-generation sequencing (NGS) has led to the discovery of a large number of genes involved in epilepsy. This may improve prompt detection of early-onset epilepsy in neonates. This study aimed at analyzing the genotype-phenotype correlations in neonates with seizures in a bid to improve the understanding of genetic diagnosis of early-onset epilepsy. Clinical features and prognosis of 15 children who underwent genetic testing having had unexplained seizures from February 2016 to May 2018 in Children's Hospital of Chongqing Medical University were analyzed retrospectively. The salient findings were: poor response to stimulus and abnormal electroencephalogram (EEG) in the initial period were observed in the group with concomitant genetic abnormalities. Despite the recent progress in genetic technology, molecular diagnosis for neonatal-onset epilepsy can be challenging due to genetic and phenotypic heterogeneities. However, some genotypes are associated with specific clinical manifestations and EEG patterns. Therefore, in-depth understanding of genotype-phenotype correlations would be useful to clinicians managing neonates with early-onset seizures.

The landscape of epilepsy-related GATOR1 variants

PurposeTo define the phenotypic and mutational spectrum of epilepsies related to DEPDC5, NPRL2 and NPRL3 genes encoding the GATOR1 complex, a negative regulator of the mTORC1 pathway MethodsWe analyzed clinical and genetic data of 73 novel probands (familial and sporadic) with epilepsy-related variants in GATOR1-encoding genes and proposed new guidelines for clinical interpretation of GATOR1 variants. ResultsThe GATOR1 seizure phenotype consisted mostly in focal seizures (e.g., hypermotor or frontal lobe seizures in 50%), with a mean age at onset of 4.4 years, often sleep-related and drug-resistant (54%), and associated with focal cortical dysplasia (20%). Infantile spasms were reported in 10% of the probands. Sudden unexpected death in epilepsy (SUDEP) occurred in 10% of the families. Novel classification framework of all 140 epilepsy-related GATOR1 variants (including the variants of this study) revealed that 68% are loss-of-function pathogenic, 14% are likely pathogenic, 15% are variants of uncertain significance and 3% are likely benign. ConclusionOur data emphasize the increasingly important role of GATOR1 genes in the pathogenesis of focal epilepsies (>180 probands to date). The GATOR1 phenotypic spectrum ranges from sporadic early-onset epilepsies with cognitive impairment comorbidities to familial focal epilepsies, and SUDEP.

Expanding the phenotype of phospholipid remodelling disease due to MBOAT7 gene defect.

MBOAT7 gene codes O-acyltransferase domain containing seven proteins which is one of four enzymes involved in remodeling of phosphoinositol phosphate (PIP) in LANDs cycle. We present clinical, neuroimaging, and genetic findings of 12 patients from 7 families with MBOAT7 gene defect, a recently defined novel phospholipid remodelling disease. To the best of our knowledge, our case series is the second report on patients with MBOAT7 gene defect. The patients present with global developmental delay particularly in speech and language skills, intellectual disability, stereotypical behavior, ataxic gait, early onset epilepsy with well response to medical treatment, strabismus and similar facial features. Common neuroimaging findings of the patients were folium dysgenesis of the cerebellum with a particular appearance, mild-to-moderate cerebellar atrophy, T2 hyperintensity of bilateral globus pallidius and dentate nuclei, enlarged perivascular areas, and mild thinning of the corpus callosum. Genome-wide genotyping and exome sequencing identified five different types of homozygous mutations in the MBOAT7 gene in all seven families which are p.Arg87*, p.Leu227ProfsX65, p.Gln376Lys, p.Trp426*, and chr19:54.666.173-54.677.766/11594 bp del. We conclude that clinical and neuroimaging findings of MBOAT7 gene defect may suggest the diagnosis and guide genetic tests.

Investigating adults with early-onset epilepsy and intellectual or physical disability

This article focuses on investigating adults with early-onset epilepsy and intellectual or physical disability within adult neurology services. We aim to guide general neurologists in the diagnostic reassessment of people...

A novel truncating mutation of DOCK7 gene with an early-onset non-encephalopathic epilepsy

A novel truncating mutation of DOCK7 gene with an early-onset non-encephalopathic epilepsy

A mutation update for the PCDH19 gene causing early-onset epilepsy in females with an unusual expression pattern.

The PCDH19 gene consists of six exons encoding a 1,148 amino acid transmembrane protein, Protocadherin 19, which is involved in brain development. Heterozygous pathogenic variants in this gene are inherited in an unusual X-linked dominant pattern in which heterozygous females are affected, while hemizygous males are typically unaffected, although they pass on the pathogenic variant to each affected daughter. PCDH19-related disorder is known to cause early-onset epilepsy in females characterized by seizure clusters exacerbated by fever and in most cases, onset is within the first year of life. This condition was initially described in 1971 and in 2008 PCDH19 was identified as the underlying genetic etiology. This condition is the result of pathogenic loss-of-function variants that may be de novo or inherited from an affected mother or unaffected father and cellular interference has been hypothesized to be the culprit. Heterozygous females are symptomatic because of the presence of both wild-type and mutant cells that interfere with one another due to the production of different surface proteins, whereas nonmosaic hemizygous males produce a homogenous population of cells. Here, we review novel pathogenic variants in the PCDH19 gene since 2012 to date, and summarize any genotype-phenotype correlations.

The Role of Protocadherin 19 (PCDH19) in Neurodevelopment and in the Pathophysiology of Early Infantile Epileptic Encephalopathy-9 (EIEE9).

PCDH19 is considered one of the most clinically relevant genes in epilepsy, second only to SCN1A. To date about 150 mutations have been identified as causative for PCDH19-female epilepsy (also known as early infantile epileptic encephalopathy-9, EIEE9), which is characterized by early onset epilepsy, intellectual disabilities, and behavioral disturbances. Although little is known about the physiological role of PCDH19 and the pathogenic mechanisms that lead to EIEE9, in this review, we will present latest researches focused on these aspects, underlining protein expression, its known functions and the mechanisms by which the protein acts, with particular interest in PCDH19 extracellular and intracellular roles in neurons.

Zebrafish studies identify serotonin receptors mediating antiepileptic activity in Dravet syndrome.

Dravet syndrome is a life-threatening early-onset epilepsy not well controlled by antiepileptic drugs. Drugs that modulate serotonin (5-HT) signalling, including clemizole, locaserin, trazodone and fenfluramine, have recently emerged as potential treatment options for Dravet syndrome. To investigate the serotonin receptors that could moderate this antiepileptic activity, we designed and synthesized 28 novel analogues of clemizole, obtained receptor binding affinity profiles, and performed in vivo screening in a scn1lab mutant zebrafish (Danio rerio) model which recapitulates critical clinical features of Dravet syndrome. We discovered three clemizole analogues with 5-HT receptor binding that exert powerful antiepileptic activity. Based on structure-activity relationships and medicinal chemistry-based analysis, we then screened an additional set of known 5-HT receptor specific drug candidates. Integrating our in vitro and in vivo data implicates 5-HT2B receptors as a critical mediator in the mechanism of seizure suppression observed in Dravet syndrome patients treated with 5-HT modulating drugs.

Compound heterozygous SZT2 mutations in two siblings with early-onset epilepsy, intellectual disability and macrocephaly

PurposeMutations in SZT2 have been previously reported in several cases of early onset epilepsy and intellectual disability. In this study we investigate potential causal mutations in two male siblings affected by early onset epilepsy, intellectual disability and macrocephaly. MethodsWe use family-based whole-exome sequencing to identify candidate variants. ResultsWe report the identification of two potential causal SZT2 mutations in compound heterozygous state. We observe considerable differences in the clinical phenotype severity of the two affected individuals. The cerebral MRI revealed no abnormalities in the older affected brother, while in the youngest one it revealed a right frontal polymicrogiria. Moreover, while good seizure control was achieved in the older affected individual the younger brother is affected by pharmacoresistant epilepsy, progressive spastic paraplegia, cortical myoclonus and a more severe intellectual disability. We also analyzed the relative location of the reported pathogenic mutations in the SZT2 protein. ConclusionVariable phenotypic expressivity is observed for this condition, while the location and type of mutations in SZT2 also has a potential impact on epilepsy severity. These findings extend our knowledge of epileptogenic conditions related to SZT2 and mTOR signaling.

Quantitative analysis and EEG markers of KCNT1 epilepsy of infancy with migrating focal seizures.

We aimed to characterize epilepsy of infancy with migrating focal seizures (EIMFS), a rare, severe early onset developmental epilepsy related to KCNT1 mutation, and to define specific electroencephalography (EEG) markers using EEG quantitative analysis. The ultimate goal would be to improve early diagnosis and to better understand seizure onset and propagation of EIMFS as compared to other early onset developmental epilepsy. EEG of 7 EIMFS patients with KCNT1 mutations (115 seizures) and 17 patients with other early onset epilepsies (30 seizures) was included in this study. After detection of seizure onset and termination, spatiotemporal characteristics were quantified. Seizure propagation dynamics were analyzed using chronograms and phase coherence. In patients with EIMFS, seizures started and were localized predominantly in temporal and occipital areas, and evolved with a stable frequency (4-10Hz). Inter- and intrahemispheric migrations were present in 60% of EIMFS seizures with high intraindividual reproducibility of temporospatial dynamics. Interhemispheric migrating seizures spread in 71% from temporal or occipital channels to the homologous contralateral ones, whereas intrahemispheric seizures involved mainly frontotemporal, temporal, and occipital channels. Causality links were present between ictal activities detected under different channels during migrating seizures. Finally, time delay index (based on delays between the different ictal onsets) and phase correlation index (based on coherence of ictal activities) allowed discrimination of EIMFS and non-EIMFS seizures with a specificity of 91.2% and a sensitivity of 84.4%. We showed that the migrating pattern in EIMFS is not a random process, as suggested previously, and that it is a particular propagation pattern that follows the classical propagation pathways. It is notable that this study reveals specific EEG markers (time delay and phase correlation) accessible to visual evaluation, which will improve EIMFS diagnosis.

Analysis of EEG networks and their correlation with cognitive impairment in preschool children with epilepsy

ObjectiveCognitive impairment (CI) is common in children with epilepsy and can have devastating effects on their quality of life. Early identification of CI is a priority to improve outcomes, but the current gold standard of detection with psychometric assessment is resource intensive and not always available. This paper proposes exploiting network analysis techniques to characterize routine clinical electroencephalography (EEG) to help identify CI in children with early-onset epilepsy (CWEOE) (0–5 years old). MethodsFunctional networks from routinely acquired EEGs of 51 newly diagnosed CWEOE were analyzed. Combinations of connectivity metrics with subnetwork analysis identified significant correlations between network properties and cognition scores via rank correlation analysis (Kendall's τ). Predictive properties were investigated using a cross-validated classification model with healthy cognition, mild/moderate CI, and severe CI classes. ResultsNetwork analysis revealed phase-dependent connectivity having higher sensitivity to CI and significant functional network changes across EEG frequencies. Nearly 70.5% of CWEOE were aptly classified as having healthy cognition, mild/moderate CI, or severe CI using network features. These features predicted CI classes 55% better than chance and halved misclassification penalties. ConclusionsCognitive impairment in CWEOE can be detected with sensitivity at 85% (in identifying mild/moderate or severe CI) and specificity of 84%, by network analysis. SignificanceThis study outlines a data-driven methodology for identifying candidate biomarkers of CI in CWEOE from network features. Following additional replication, the proposed method and its use of routinely acquired EEG forms an attractive proposition for supporting clinical assessment of CI.

Experiences and needs of parents of young children with active epilepsy: A population-based study

The aim of the study was to gain a comprehensive understanding of the experiences and needs of parents of young children with epilepsy from a total population sample. The parents (mothers (n = 38), fathers (n = 9)) of 40/53 (75% of total population) young children (1–7 years; 23 males, 17 females) with ‘active’ epilepsy (had a seizure in the last year or taking Anti-epileptic drugs (AEDs)) were interviewed either in person or over the telephone using a semistructured interview schedule. The families were resident in the south of the UK. The interviews were audio-recorded, transcribed, and coded using thematic analysis. Thematic analysis revealed six main themes: diagnostic journey, parental perception of epilepsy management, awareness and impact of associated neurobehavioral difficulties, inconsistent availability of therapeutic and educational supports, impact on family functioning, and need for parental support. Parents reported often having difficulty accessing a professional knowledgeable about epilepsy. While parents were generally satisfied with the initial information they received about seizures and their management, they reported that the association between epilepsy and neurobehavioral issues was often not broached. These developmental/behavioral difficulties often had a bigger impact on child wellbeing and family functioning, but provision of therapeutic and educational supports for the difficulties was often very patchy. Parents noted that early onset epilepsy and associated neurobehavioral difficulties often have a very significant impact on family functioning including increased restrictions on family activities and increased financial burden. Parents would like informational and emotional support to extend beyond the time of epilepsy diagnosis. There is a clear need for comprehensive childhood epilepsy services to include provision for identification and management of child neurobehavioral needs and a focus on family-centered care.

Progressive myoclonus epilepsy and ceroidolipofuscinosis 14: The multifaceted phenotypic spectrum of KCTD7-related disorders

BackgroundMutations in the KCTD7 gene have been associated with progressive myoclonus epilepsy and, in a single patient, with the so-called “Neuronal Ceroid Lipofuscinosis 14” (characterised by myoclonic seizures, cognitive regression, optic atrophy leading to visual loss, and progressive cortical and cerebellar atrophy). Clinical reportsWe describe two new patients carrying two novel pathogenic mutations in the KCTD7 gene. Patient 1 (NM_153033.4: c.[533C > T], NP_694578: p.[(Ala178Val)]) was a 17-year-old girl who presented with early-onset epilepsy resembling epilepsia partialis continua (responsive to intravenous corticosteroids and immunoglobulins), and later developed myoclonic seizures and atypical absences, photosensitivity to very low frequencies and progressive seizures-related neurocognitive and motor deterioration. Patient 2 (NM_153033.4: c.[172G>A], NP_694578: p.[(Gly58Arg)]) presented with early neurological regression, myoclonic seizures and lysosomal storage material which was consistent with a neuronal ceroid lipofuscinosis (NCL) at skin biopsy. Both patients had non epileptic myoclonus. ConclusionsThe two reported patients carrying novel pathogenic variants in KCTD7 gene presented with a remarkable phenotypic heterogeneity including: a) progressive myoclonus epilepsy without NCL-type lysosomal storages; b) progressive myoclonus epilepsy with lysosomal storages resembling NCL pattern (NCL14); c) progressive myoclonus epilepsy with epilepsia partialis continua.

Etiologies of neonatal seizures in infants of different gestational age

Aim:To determine main etiologies and clinical features of neonatal seizures (NS) in groups of newborns of different gestational age (GA).Materials and Methods. Main etiologies of NS were evaluated in 165 newborns divided into four groups: I – 84 early preterm newborns with GA of 28 weeks or less, II – 52 newborns with 29-32 weeks GA, III – 12 newborns with 33-36 weeks GA, and IV – 17 term infants with GA between 37 and 41 wks.Results. In the above 165 infants, the following causes of NS were found: perinatal hypoxia-ischemia – 72.1% of cases, grade III-IV intracranial hemorrhage – 6.1%, congenital infections in 9.7%, CNS infections (bacterial meningitis and viral meningoencephalitis) – 9.7%, сerebral dysgenesis – 1.2%, and inborn errors of metabolism and neurodegenerative diseases accounted for 1.2%. Intracranial hemorrhage (grade III-IV) was detected in newborns with GA less than 32 wks only. The etiological role of CNS infections was higher in term newborns (23.5%) than in the other groups.Conclusion.In examining newborns with NS, genetic mechanisms should be taken into consideration, especially when no indications of early brain damage are apparent. This approach is important today as targeted therapies of gene-associated epileptic syndromes are becoming feasible. In the present article, the use of levetiracetam in infants with NS and early onset epilepsy is discussed.