The Genetics of Epilepsy Perucca, Piero; Bahlo, Melanie; Berkovic, Samuel F
Annual review of genomics and human genetics,
08/2020, Letnik:
21, Številka:
1
Journal Article
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Epilepsy encompasses a group of heterogeneous brain diseases that affect more than 50 million people worldwide. Epilepsy may have discernible structural, infectious, metabolic, and immune etiologies; ...however, in most people with epilepsy, no obvious cause is identifiable. Based initially on family studies and later on advances in gene sequencing technologies and computational approaches, as well as the establishment of large collaborative initiatives, we now know that genetics plays a much greater role in epilepsy than was previously appreciated. Here, we review the progress in the field of epilepsy genetics and highlight molecular discoveries in the most important epilepsy groups, including those that have been long considered to have a nongenetic cause. We discuss where the field of epilepsy genetics is moving as it enters a new era in which the genetic architecture of common epilepsies is starting to be unraveled.
Genomics now has an increasingly important role in neurology clinics. Regarding the epilepsies, innovations centred around technology, analytics, and collaboration have led to remarkable progress in ...gene discovery and have revealed the diverse array of genetic mechanisms and neurobiological pathways that contribute to these disorders. The new genomic era can present a challenge to clinicians, who now find themselves asked to interpret and apply genetic data to their daily management of patients with epilepsy. Navigation of this new era will require genetic literacy and familiarity with research advances in epilepsy genetics. Genetic epilepsy diagnoses now directly affect clinical care, and their importance will only increase as new targeted treatments continue to emerge. At the same time, new genetic insights challenge us to move from a deterministic view of genetic changes to a more nuanced appreciation of genetic risk within complex neurobiological systems that give rise to epilepsy.
We performed hypothesis-free linkage analysis and exome sequencing in a family with two siblings who had neuronal ceroid lipofuscinosis (NCL). Two linkage peaks with maximum LOD scores of 3.07 and ...2.97 were found on chromosomes 7 and 17, respectively. Unexpectedly, we found these siblings to be homozygous for a c.813_816del (p.Thr272Serfs∗10) mutation in the progranulin gene (GRN, granulin precursor) in the latter peak. Heterozygous mutations in GRN are a major cause of frontotemporal lobar degeneration with TDP-43 inclusions (FTLD-TDP), the second most common early-onset dementia. Reexamination of progranulin-deficient mice revealed rectilinear profiles typical of NCL. The age-at-onset and neuropathology of FTLD-TDP and NCL are markedly different. Our findings reveal an unanticipated link between a rare and a common neurological disorder and illustrate pleiotropic effects of a mutation in the heterozygous or homozygous states.
Inhibitory interneurons shape the spiking characteristics and computational properties of cortical networks. Interneuron subtypes can precisely regulate cortical function but the roles of interneuron ...subtypes for promoting different regimes of cortical activity remains unclear. Therefore, we investigated the impact of fast spiking and non-fast spiking interneuron subtypes on cortical activity using a network model with connectivity and synaptic properties constrained by experimental data. We found that network properties were more sensitive to modulation of the fast spiking population, with reductions of fast spiking excitability generating strong spike correlations and network oscillations. Paradoxically, reduced fast spiking excitability produced a reduction of global excitation-inhibition balance and features of an inhibition stabilised network, in which firing rates were driven by the activity of excitatory neurons within the network. Further analysis revealed that the synaptic interactions and biophysical features associated with fast spiking interneurons, in particular their rapid intrinsic response properties and short synaptic latency, enabled this state transition by enhancing gain within the excitatory population. Therefore, fast spiking interneurons may be uniquely positioned to control the strength of recurrent excitatory connectivity and the transition to an inhibition stabilised regime. Overall, our results suggest that interneuron subtypes can exert selective control over excitatory gain allowing for differential modulation of global network state.
Familial adult myoclonus epilepsy/benign adult familial myoclonic epilepsy (FAME/BAFME) has emerged as a specific and recognizable epilepsy syndrome with autosomal dominant inheritance found around ...the world. Here, we trace the history of this syndrome. Initially, it was likely conflated with other familial myoclonus epilepsies, especially the progressive myoclonus epilepsies. As the progressive myoclonus epilepsies became better understood clinically and genetically, this group began to stand out and was first recognized as such in Japan. Subsequently, families were recognized around the world and there was debate as to whether they represented one or multiple disorders. Clarification came with the identification of pentanucleotide repeats in Japanese families, and FAME/BAFME was quickly shown to be due to pentanucleotide expansions in at least six genes. These have geographic predilections and appear to have been caused by historically ancient initial mutations. Within and between families, there is some variation in the phenotype, explained in large part by expansion size, but whether there are features specific to individual genes remains uncertain.
Understanding the aetiology of epilepsy is essential both for clinical management of patients and for conducting neurobiological research that will direct future therapies. The aetiology of epilepsy ...was formerly regarded as unknown in about three-quarters of patients; however, massively parallel gene-sequencing studies, conducted in a framework of international collaboration, have yielded a bounty of discoveries that highlight the importance of gene mutations in the aetiology of epilepsy. These data, coupled with clinical genetic studies, suggest a new paradigm for use in the clinic: many forms of epilepsy are likely to have a genetic basis. Enquiry about a genetic cause of epilepsy is readily overlooked in the clinic for a number of understandable but remediable reasons, not least an incomplete understanding of its genetic architecture. In addition, the importance of de novo mutagenesis is often underappreciated, particularly in the epileptic encephalopathies. Other genomic surprises are worth emphasizing, such as the emerging evidence of a genetic contribution to focal epilepsies-long regarded as acquired conditions-and the complex role of copy number variation. The importance of improved understanding of the genetics of the epilepsies is confirmed by the positive outcomes, in terms of treatment selection and counselling, of receiving a genetic diagnosis.
Gene panel and exome sequencing have revealed a high rate of molecular diagnoses among diseases where the genetic architecture has proven suitable for sequencing approaches, with a large number of ...distinct and highly penetrant causal variants identified among a growing list of disease genes. The challenge is, given the DNA sequence of a new patient, to distinguish disease-causing from benign variants. Large samples of human standing variation data highlight regional variation in the tolerance to missense variation within the protein-coding sequence of genes. This information is not well captured by existing bioinformatic tools, but is effective in improving variant interpretation. To address this limitation in existing tools, we introduce the missense tolerance ratio (MTR), which summarizes available human standing variation data within genes to encapsulate population level genetic variation. We find that patient-ascertained pathogenic variants preferentially cluster in low MTR regions (
< 0.005) of well-informed genes. By evaluating 20 publicly available predictive tools across genes linked to epilepsy, we also highlight the importance of understanding the empirical null distribution of existing prediction tools, as these vary across genes. Subsequently integrating the MTR with the empirically selected bioinformatic tools in a gene-specific approach demonstrates a clear improvement in the ability to predict pathogenic missense variants from background missense variation in disease genes. Among an independent test sample of case and control missense variants, case variants (0.83 median score) consistently achieve higher pathogenicity prediction probabilities than control variants (0.02 median score; Mann-Whitney
test,
< 1 × 10
). We focus on the application to epilepsy genes; however, the framework is applicable to disease genes beyond epilepsy.
Epilepsy is a common and serious neurologic disease with a strong genetic component. Genetic studies have identified an increasing collection of disease-causing genes. The impact of these genetic ...discoveries is wide reaching-from precise diagnosis and classification of syndromes to the discovery and validation of new drug targets and the development of disease-targeted therapeutic strategies. About 25% of genes identified in epilepsy encode ion channels. Much of our understanding of disease mechanisms comes from work focused on this class of protein. In this study, we review the genetic, molecular, and physiologic evidence supporting the pathogenic role of a number of different voltage- and ligand-activated ion channels in genetic epilepsy. We also review proposed disease mechanisms for each ion channel and highlight targeted therapeutic strategies.
...recently, infants with severe epilepsy and intellectual disability often received a diagnosis of not much more than that—the cause was usually unknown, treatment was supportive, and families often ...felt disempowered due to lack of information about the condition. First recognised clinically by Charlotte Dravet in 1978, the syndrome was largely ignored by child neurologists as the relatively complex clinical pattern accurately described by Dravet did not agree with diagnostic thinking. Among conventional anti-epileptic drugs, valproate, topiramate, and clobazam are believed to be most effective (without class 1 evidence), whereas sodium channel blockers such as lamotrigine, carbamazepine, and phenytoin should be avoided.5 Until now, only stiripentol and cannabidiol had robust evidence of efficacy,6–8 and some believe that suppression of seizures does lead to better overall outcome.
Summary Background Seizure prediction would be clinically useful in patients with epilepsy and could improve safety, increase independence, and allow acute treatment. We did a multicentre clinical ...feasibility study to assess the safety and efficacy of a long-term implanted seizure advisory system designed to predict seizure likelihood and quantify seizures in adults with drug-resistant focal seizures. Methods We enrolled patients at three centres in Melbourne, Australia, between March 24, 2010, and June 21, 2011. Eligible patients had between two and 12 disabling partial-onset seizures per month, a lateralised epileptogenic zone, and no history of psychogenic seizures. After devices were surgically implanted, patients entered a data collection phase, during which an algorithm for identification of periods of high, moderate, and low seizure likelihood was established. If the algorithm met performance criteria (ie, sensitivity of high-likelihood warnings greater than 65% and performance better than expected through chance prediction of randomly occurring events), patients then entered an advisory phase and received information about seizure likelihood. The primary endpoint was the number of device-related adverse events at 4 months after implantation. Our secondary endpoints were algorithm performance at the end of the data collection phase, clinical effectiveness (measures of anxiety, depression, seizure severity, and quality of life) 4 months after iniation of the advisory phase, and longer-term adverse events. This trial is registered with ClinicalTrials.gov , number NCT01043406. Findings We implanted 15 patients with the advisory system. 11 device-related adverse events were noted within four months of implantation, two of which were serious (device migration, seroma); an additional two serious adverse events occurred during the first year after implantation (device-related infection, device site reaction), but were resolved without further complication. The device met enabling criteria in 11 patients upon completion of the data collection phase, with high likelihood performance estimate sensitivities ranging from 65% to 100%. Three patients' algorithms did not meet performance criteria and one patient required device removal because of an adverse event before sufficient training data were acquired. We detected no significant changes in clinical effectiveness measures between baseline and 4 months after implantation. Interpretation This study showed that intracranial electroencephalographic monitoring is feasible in ambulatory patients with drug-resistant epilepsy. If these findings are replicated in larger, longer studies, accurate definition of preictal electrical activity might improve understanding of seizure generation and eventually lead to new management strategies. Funding NeuroVista.
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