Cognitive and neurodevelopmental comorbidities in paediatric epilepsy

Nickels, Katherine C.; Zaccariello, Michael J.; Hamiwka, Lorie; Wirrell, Elaine

doi:10.1038/nrneurol.2016.98

Cited by 177 publications

(138 citation statements)

References 140 publications

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“…Repeated and refractory seizures can cause long-term cognitive impairment, decreased social participation and significantly lower quality of life [1, 2]. Epilepsy is one of the most common neurological disorders with 50 to 100 million affected worldwide, and 2 to 4 million new cases diagnosed each year [3].…”

Section: Introductionmentioning

confidence: 99%

Novel and de novo mutations in pediatric refractory epilepsy

et al. 2018

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Pediatric refractory epilepsy is a broad phenotypic spectrum with great genetic heterogeneity. Next-generation sequencing (NGS) combined with Sanger sequencing could help to understand the genetic diversity and underlying disease mechanisms in pediatric epilepsy. Here, we report sequencing results from a cohort of 172 refractory epilepsy patients aged 0–14 years. The pathogenicity of identified variants was evaluated in accordance with the American College of Medical Genetics and Genomics (ACMG) criteria. We identified 43 pathogenic or likely pathogenic variants in 40 patients (23.3%). Among these variants, 74.4% mutations (32/43) were de novo and 60.5% mutations (26/43) were novel. Patients with onset age of seizures ≤12 months had higher yields of deleterious variants compared to those with onset age of seizures > 12 months (P = 0.006). Variants in ion channel genes accounted for the greatest functional gene category (55.8%), with SCN1A coming first (16/43). 81.25% (13/16) of SCN1A mutations were de novo and 68.8% (11/16) were novel in Dravet syndrome. Pathogenic or likely pathogenic variants were found in the KCNQ2, STXBP1, SCN2A genes in Ohtahara syndrome. Novel deleterious variants were also found in West syndrome, Doose syndrome and glucose transporter type 1 deficiency syndrome patients. One de novo MECP2 mutation were found in a Rett syndrome patient. TSC1/TSC2 variants were found in 60% patients with tuberous sclerosis complex patients. Other novel mutations detected in unclassified epilepsy patients involve the SCN8A, CACNA1A, GABRB3, GABRA1, IQSEC2, TSC1, VRK2, ATP1A2, PCDH19, SLC9A6 and CHD2 genes. Our study provides novel insights into the genetic origins of pediatric epilepsy and represents a starting-point for further investigations into the molecular pathophysiology of pediatric epilepsy that could eventually lead to better treatments.Electronic supplementary materialThe online version of this article (10.1186/s13041-018-0392-5) contains supplementary material, which is available to authorized users.

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Section: Introductionmentioning

confidence: 99%

Novel and de novo mutations in pediatric refractory epilepsy

et al. 2018

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“…Our previous work showed that adult APC cKO cortical and hippocampal pyramidal neurons exhibit an increased density of excitatory synaptic spines, with no change in paired pulse facilitation arguing against a change in pre-synaptic function (Mohn JL et al 2014). Previously, we also demonstrated that adult APC cKO mice display cognitive and autistic disabilities (Mohn JL et al 2014), which are often co-morbid with IS in humans (Kim EH and TS Ko 2016; Nickels KC et al 2016). Together, our findings provide novel insights into the consequences of deregulated β-catenin pathways in early brain development and suggest that these pathways may be central to the pathophysiology of IS.…”

Section: Discussionmentioning

confidence: 82%

APC conditional knock-out mouse is a model of infantile spasms with elevated neuronal β-catenin levels, neonatal spasms, and chronic seizures

Pirone

Alexander

Lau

et al. 2017

Neurobiology of Disease

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Infantile spasms (IS) are a catastrophic childhood epilepsy syndrome characterized by flexion-extension spasms during infancy that progress to chronic seizures and cognitive deficits in later life. The molecular causes of IS are poorly defined. Genetic screens of individuals with IS have identified multiple risk genes, several of which are predicted to alter β-catenin pathways. However, evidence linking malfunction of β-catenin pathways and IS is lacking. Here, we show that conditional deletion in mice of the adenomatous polyposis coli gene (APC cKO), the major negative regulator of β-catenin, leads to excessive β-catenin levels and multiple salient features of human IS. Compared with wild-type littermates, neonatal APC cKO mice exhibit flexion-extension motor spasms and abnormal high-amplitude electroencephalographic discharges. Additionally, the frequency of excitatory postsynaptic currents is increased in layer V pyramidal cells, the major output neurons of the cerebral cortex. At adult ages, APC cKOs display spontaneous electroclinical seizures. These data provide the first evidence that malfunctions of APC/β-catenin pathways cause pathophysiological changes consistent with IS. Our findings demonstrate that the APC cKO is a new genetic model of IS, provide novel insights into molecular and functional alterations that can lead to IS, and suggest novel targets for therapeutic intervention.

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“…Cognitive comorbidities in individuals with epilepsy often include memory problems . However, the mechanisms underlying memory deficits in epilepsy are not understood.…”

Section: Introductionmentioning

confidence: 99%

Ripple‐related firing of identified deep CA1 pyramidal cells in chronic temporal lobe epilepsy in mice

et al. 2019

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Summary Objective Temporal lobe epilepsy (TLE) is often associated with memory deficits. Reactivation of memory traces in the hippocampus occurs during sharp‐wave ripples (SWRs; 140‐250 Hz). To better understand the mechanisms underlying high‐frequency oscillations and cognitive comorbidities in epilepsy, we evaluated how rigorously identified deep CA1 pyramidal cells (dPCs) discharge during SWRs in control and TLE mice. Methods We used the unilateral intraamygdala kainate model of TLE in video–electroencephalography (EEG) verified chronically epileptic adult mice. Local field potential and single‐cell recordings were performed using juxtacellular recordings from awake control and TLE mice resting on a spherical treadmill, followed by post hoc identification of the recorded cells. Results Hippocampal SWRs in TLE mice occurred with increased intraripple frequency compared to control mice. The frequency of SWR events was decreased, whereas the overall frequency of SWRs, interictal epileptiform discharges, and high‐frequency ripples (250‐500 Hz) together was not altered. CA1 dPCs in TLE mice showed significantly increased firing during ripples as well as between the ripple events. The strength of ripple modulation of dPC discharges increased in TLE without alteration of the preferred phase of firing during the ripple waves. Significance These juxtacellular electrophysiology data obtained from identified CA1 dPCs from chronically epileptic mice are in general agreement with recent findings indicating distortion of normal firing patterns during offline SWRs as a mechanism underlying deficits in memory consolidation in epilepsy. Because the primary seizure focus in our experiments was in the amygdala and we recorded from the CA1 region, these results are also in agreement with the presence of altered high‐frequency oscillations in areas of secondary seizure spread.

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Cognitive and neurodevelopmental comorbidities in paediatric epilepsy

Cited by 177 publications

References 140 publications

Novel and de novo mutations in pediatric refractory epilepsy

Novel and de novo mutations in pediatric refractory epilepsy

APC conditional knock-out mouse is a model of infantile spasms with elevated neuronal β-catenin levels, neonatal spasms, and chronic seizures

Ripple‐related firing of identified deep CA1 pyramidal cells in chronic temporal lobe epilepsy in mice

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