Epilepsia
Ohtahara syndrome (OS) is one of the most severe and earliest forms of epilepsy. De novo heterozygous mutations and a microdeletion of STXBP1 have been found in individuals with OS. STXBP1 encodes MUNC18‐1, which is essential in synaptic vesicle release, highlighting aberration of synaptic vesicle release in pathogenesis of epilepsy. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
Epilepsy occurs frequently in individuals with autism spectrum disorders (ASDs). However, the mechanisms responsible for increased seizure susceptibility in ASDs are largely unknown. Clues to neural hyperexcitability in the autistic brain might be derived from disorders in which single gene mutations cause both epilepsy and an autistic phenotype, such as fragile X syndrome. For an expanded treatment...
Unverricht‐Lundborg disease is a neurodegenerative disorder characterized by stimulus‐sensitive myoclonus, epileptic seizures, and ataxia. It is associated with mutations in the Cystatin B gene. The neuronal ceroid lipofuscinoses are a heterogeneous group of disorders characterized by the intracellular accumulation of autofluorescent lipopigment. Mutations in eight genes have been identified. For...
The common forms of idiopathic epilepsies have complex genetic inheritance and are likely to include genes in biologic pathways other than “channelopathies,” the most frequent cause of their rare Mendelian counterparts. Recent analyses of ELP4 and BRD2 indicate that subtle genetically determined neurodevelopmental deviations may play a part in the pathogenesis of rolandic epilepsy and juvenile myoclonic...
Tuberous sclerosis complex and related malformations of cortical development represent common developmental causes of intractable epilepsy. Abnormalities in the mammalian target of rapamycin pathway may be central to the pathophysiology of epilepsy and other neurologic deficits in these disorders and serve as a rational target for antiepileptogenic or disease‐modifying therapies. For an expanded treatment...
GABRB3 is important to neurodevelopment, and appears to be influenced by non‐Mendelian and epigenetic mechanisms. GABRB3 abnormalities have been implicated in a variety of neurodevelopmental conditions presenting epilepsy phenotypes, including childhood absence epilepsy, Angelman syndrome, and autism. Gabrb3 disruption in mice also results in seizure phenotypes, ataxia, and sensory and learning disorders...
Myoclonin1/EFHC1 mutations cause 9% of juvenile myoclonic epilepsy (JME) by impairing apoptosis in neurons/synapses where R type voltage dependent calcium channel function is altered, imbuing susceptibility to myoclonic and grand mal seizures. By disrupting mitotic spindle assembly and radial migration of neuroblasts, mutations could produce abnormal intracortical architecture upon which epileptogenesis...
Glial cells have both beneficial and detrimental effects on recovery from brain damage and play a role in epileptogenesis. Herein, we summarize evidence indicating that the ability of astrocytes to produce neurosteroids that reinforce γ‐aminobutyric acid receptor A (GABAA) functions impinge on epileptogenesis, as shown in temporal lobe epilepsy models. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
The potassium channel family represents a large group with diverse functional roles. Not surprisingly, the list of potassium channelopathies contributing to human epilepsy has greatly expanded. The focus of this chapter will be the causative role in epilepsy of mutations in potassium channels and associated regulatory proteins. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
Although multiple genes drive epileptogenesis, uncovering the mechanisms controlling expression of GABAA receptors (GABAARs), the brain’s major inhibitory receptors, may have far‐reaching therapeutic implications. In this review, we describe how seizure‐induced changes in GABAARs result from brain‐derived neurotrophic factor (BDNF)‐induced changes in Janus kinase/Signal Transducer and Activators of...
Recent advances in the understanding of the physiology of astrocytes have identified unexpected potential roles for glia in epilepsy. Reactive astrocytosis, as seen in epilepsy, leads to reduced adenosine‐ and γ‐aminobutyric acid (GABA)–dependent inhibition. Because astrocytes express cell‐type specific proteins, the new findings raise the potential of new targets for drug development. For an expanded...
Voltage‐gated Na+ channels are the molecular targets for mutations that cause several epilepsy syndromes. Mutations that impair the function of NaV1.1 channels cause reduced Na+ currents and failure of electrical excitability in γγ‐aminobutyric acid (GABA)ergic interneurons, providing a potential mechanism for hyperexcitability in a spectrum of Na+ channel epilepsy syndromes. For an expanded treatment...
Identifying the genes that influence risk for genetically complex epilepsies is a major challenge for the next decade. This chapter reviews possible biologic mechanisms, methodologic approaches, and findings from recent studies aimed at gene identification in complex epilepsies, and approaches for clarifying phenotype definition for genetic research on the epilepsies. For an expanded treatment of...
Most human epilepsies are multifactorial, resulting from combined effects of genes and environment. The large number of genes whose variation and/or mutation influences the development and progression of epilepsy are only now beginning to be identified. Advanced methods of genetic analysis promise to facilitate understanding of pathogenesis and establishment of new effective treatments. For an expanded...
Two electron‐neutral, cation‐chloride cotransporters control intraneuronal chloride ion concentration (Cl−). The Na‐K‐2Cl cotransporter‐1 mediates Cl− influx while the K‐Cl cotransporter‐2 (KCC2) extrudes Cl−, assuring that γ‐aminobutyric acid (GABA)ergic signals hyperpolarize neurons. KCC2 is downregulated in pyramidal cells from human temporal lobe epilepsy and experimental focal epilepsy, inducing...
Administration of kainic acid generates a syndrome of seizures and brain damage that mimics temporal lobe epilepsy (TLE) and has provided many basic concepts of relevant to the epilepsies—mechanisms of cell death, failure of inhibition, sprouting and neosynapse formation, and how seizures begets seizures. In addition, kainatergic synapses are enriched on vulnerable neurons, a form of plasticity that...
The histopathology of the hippocampus of patients with temporal lobe epilepsy shows two major processes. One involves reorganization of neural circuits in the dentate gyrus and the other a proliferation of reactive astrocytes that have many unusual properties. These modified astrocytes may play a major role in creating an epileptic focus. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
The neurobiologic basis for infantile spasms has long been debated but with little resolution. The very recent development of several animal models of this disorder should provide a paradigm shift in our understanding of this disorder. This chapter outlines unresolved questions and suggests experimental approaches to answering them. For an expanded treatment of this topic see Jasper’s Basic Mechanisms of the Epilepsies, Fourth Edition...
This chapter reviews current computational models and proposes future directions for computational modeling in the field of epilepsy. The models include single cells with mutated ion channels; small‐ and large‐scale networks of detailed cells; and macroscopic, mean‐field models of network dynamics. In addition, we consider the potential therapeutic applications of modeling. For an expanded treatment...
γ‐Aminobutyric acid (GABA) is the main inhibitory transmitter in the central nervous system (CNS) and regulates via GABAA receptors tonic and phasic inhibition. This review focuses on the sequential steps leading to phasic inhibition, including vesicle exocytosis, dynamics of GABA transient in the synaptic cleft, binding to GABAA receptors, opening of anionic channels, and neurotransmitter clearance...