Epilepsy genetics: clinical impacts and biological insights

Ellis, Colin A; Petrovski, Steve; Berkovic, Samuel F.

doi:10.1016/s1474-4422(19)30269-8

Cited by 98 publications

(95 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Identifying and modeling germline mutations associated with developmental and epileptic encephalopathies provides the unique opportunity to develop targeted therapeutics 51 . While the 260 majority of these mutations tend to occur in genes that encode ion channels or synaptic transmission proteins, a subset of these genes can be thought of as causing disease through their effects on the transcriptome 52,53 . Unfortunately, elucidating disease mechanisms for this subset of genes is often difficult, as the encoded proteins regulate the expression of thousands of target genes.…”

Section: Discussionmentioning

confidence: 99%

Neurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model ofHNRNPUhaploinsufficiency

Dugger

Dhindsa

Sampaio

et al. 2020

Preprint

View full text Add to dashboard Cite

Heterozygous de novo loss-of-function mutations in the gene expression regulator HNRNPU cause an early-onset developmental and epileptic encephalopathy. To gain insight into pathological mechanisms and lay the groundwork for developing targeted therapies, we characterized the neurophysiologic and cell-type-specific transcriptomic consequences of a mouse model of HNRNPU haploinsufficiency. Heterozygous mutants demonstrated 5 neuroanatomical abnormalities, global developmental delay and impaired ultrasonic vocalizations, and increased seizure susceptibility, thus modeling aspects of the human disease. Single-cell RNA-sequencing of hippocampal and neocortical cells revealed widespread, yet modest, dysregulation of gene expression across mutant neuronal subtypes. We observed an increased burden of differentially-expressed genes in mutant excitatory neurons of the 10 subiculum-a region of the hippocampus implicated in temporal lobe epilepsy. Evaluation of transcriptomic signature reversal as a therapeutic strategy highlighted the potential importance of generating cell-type-specific signatures. Overall, this work provides insight into HNRNPUmediated disease mechanisms, and provides a framework for using single-cell RNA-sequencing to study transcriptional regulators implicated in disease. chromatin organization 17,18 . We and others have reported de novo loss-of-function variants [19][20][21][22][23] and microdeletions 24,25 encompassing HNRNPU in pediatric patients with a severe, and often treatment refractory, developmental and epileptic encephalopathy (DEE) characterized by earlyonset epilepsy, moderate to severe developmental delay, autistic features, structural brain abnormalities, hypotonia, short stature and variable renal and cardiac abnormalities. HnRNP U is 35 essential for mammalian development as lethality results by embryonic day 11.5 in mice carrying homozygous hypomorphic mutations 26 . Furthermore, homozygous pathogenic mutations have yet to be reported in humans 27 . Conditional loss of Hnrnpu in mouse cardiomyocytes was also associated with a lethal dilated cardiomyopathy and widespread transcriptional and splicing 3 dysregulation including known cardiomyopathy disease genes 16 . However, the transcriptomic and 40 physiologic effects of Hnrnpu haploinsufficiency in the brain have yet to be characterized.Here we assess the neurophysiological consequences and face validity of an Hnrnpu mouse disease model using in vivo developmental, morphological, electrophysiological, and behavioral studies. We also perform a comprehensive cell-type-and brain region-specific characterization of reduced Hnrnpu levels on gene expression using scRNAseq. Using these 45 data, we generate cell-type-specific disease expression signatures and identify vulnerable cell types in the mutant mouse brain. We then compare these signatures to publicly-available gene expression signatures of cells treated with small molecules in order to identify compounds that correct disease-associated transcriptomic changes towards a normal state. ...

show abstract

Section: Discussionmentioning

confidence: 99%

Neurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model ofHNRNPUhaploinsufficiency

Dugger

Dhindsa

Sampaio

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Newer treatment options therefore should be explored. The discovery of genetic variations/mutations as the cause of epilepsy in many young children with epilepsy is a doorway to precision treatment (Ellis et al 2019, Sisodiya et al, 2019, Orsini et al, 2019, Kearney et al, 2019, Fitzgerald et al, 2019, Truty et al, 2019, Milh et al, 2016. With the advances in understanding the molecular basis of many epilepsies, targeted therapies become available, in contrast with the broad-spectrum non-specific efficacy of most existing drugs.…”

Section: Precision Medicinementioning

confidence: 99%

Why we urgently need improved seizure and epilepsy therapies for children and neonates

Pressler

Lagae

2020

Neuropharmacology

View full text Add to dashboard Cite

In contrast to epilepsy in adolescents and adults, neonatal seizures and early onset epilepsy poses unique challenges with significant repercussion for treatment choices. Most importantly, high seizure burden and epileptic encephalopathy are associated with developmental, behavioural and cognitive problems. The causes are multifactorial and include etiology, seizure burden, epileptic encephalopathy, but also antiseizure medication. In contrast to adults and older children only very few drugs have been licenced for infants and neonates, and after a long delay. Very recently, extrapolation of adult data has become possible as a path to speed up drug development for younger children but this is not necessarily possible for infants and neonates. With the advances in understanding the molecular basis of many epilepsies, targeted therapies become available, for example for KCNQ2 mutation related epilepsies, Dravet syndrome or tuberous sclerosis complex. Drug trials in neonates are particularly challenging because of their inconspicuous clinical presentation, the need for continuous EEG monitoring, high co-morbidity, and poor response to antiepileptic drugs. There is an urgent need for development of new drugs, evaluation of safety and efficacy of current antiseizure drugs, as well as for national policies and guidelines for the management of seizures and epilepsy in neonates and infants. Highlights  Treatment of early onset seizures and epilepsies pose a clinical challenge to clinicians.  Only very few drugs have been licenced due to lack of randomised controlled trials.  Systematic reviews no good evidence for the choice of treatment.  Precision medicine is so far only available for a small number of syndromes.

show abstract

“…mechanisms underlying ictogenesis and epileptogenesis by identifying novel genetic loci and profound changes in gene expression in humans and animal models [19][20][21][22][23][24]. However, the poor correlation between RNA expression and protein levels limits the value of isolated transcriptomic or genomic studies [25].…”

mentioning

confidence: 99%

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Pires

Leitner

Drummond

et al. 2020

Preprint

View full text Add to dashboard Cite

Epilepsy is a common neurological disorder affecting over 70 million people worldwide, with a high rate of pharmaco-resistance, diverse comorbidities including progressive cognitive and behavioral disorders, and increased mortality from direct (e.g., Sudden Unexpected Death in Epilepsy [SUDEP], accidents, drowning) or indirect effects of seizures and therapies. Extensive research with animal models and human studies provides limited insights into the mechanisms underlying seizures and epileptogenesis, and these have not translated into significant reductions in pharmaco-resistance, morbidities or mortality. To help define changes in molecular signaling networks associated with epilepsy, we examined the proteome of brain samples from epilepsy and control cases. Label-free quantitative mass spectrometry (MS) was performed on the hippocampal CA1-3 region, frontal cortex, and dentate gyrus microdissected from epilepsy and control cases (n=14/group). Epilepsy cases had significant differences in the expression of 777 proteins in the hippocampal CA1-3 region, 296 proteins in the frontal cortex, and 49 proteins in the dentate gyrus in comparison to control cases. Network analysis showed that proteins involved in protein synthesis, mitochondrial function, G-protein signaling, and synaptic plasticity were particularly altered in epilepsy. While protein differences were most pronounced in the hippocampus, similar changes were observed in other brain regions indicating broad proteomic abnormalities in epilepsy. Among the most significantly altered proteins, G-protein Subunit Beta 1 (GNB1) was one of the most significantly decreased proteins in epilepsy in all regions studied, highlighting the importance of G-protein subunit signaling and G-protein–coupled receptors (GPCRs) in epilepsy. Our results provide insights into the molecular mechanisms underlying epilepsy, which may allow for novel targeted therapeutic strategies.

show abstract

Epilepsy genetics: clinical impacts and biological insights

Cited by 98 publications

References 70 publications

Neurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model ofHNRNPUhaploinsufficiency

Neurodevelopmental deficits and cell-type-specific transcriptomic perturbations in a mouse model ofHNRNPUhaploinsufficiency

Why we urgently need improved seizure and epilepsy therapies for children and neonates

Proteomic Differences in the Hippocampus and Cortex of Epilepsy Brain Tissue

Contact Info

Product

Resources

About