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  • Heredity represents the single largest etiology of the epilepsies, a common and extremely heterogeneous set of neurologic disorders defined by repeated clinical seizure episodes linked to aberrant electrical synchronization of the brain. Like cardiac arrhythmias, epileptic seizures display distinctive electrographic patterns that reflect signaling abnormalities within critical cortical networks. The seizures are due to primary molecular defects intrinsic to neurons or glia that alter membrane or synaptic excitability, or to induced excitability fluctuations when these circuits become the downstream targets of developmental or metabolic disturbances.

  • Genetic transmission patterns of epilepsy are both Mendelian and complex; most cases are sporadic. Currently recognized monogenic syndromes represent a small subset of all epilepsies. While some phenotypes are comprised only of seizures, in many syndromes, epilepsy is only one highly variable element of a broader clinical spectrum, because genes associated with epilepsy may be expressed in both neural and nonneural tissues.

  • Epileptic seizures are categorized by the extent of their cerebral involvement (partial or generalized); by the sparing or impairment of consciousness (simple or complex); and by the pattern of associated motor activity (atonic, astatic, tonic, clonic, arrest). Clinical epilepsy syndromes are defined by the seizure type, natural history, precipitating factors, drug sensitivity, and the presence of associated neurologic deficits. In benign epilepsy syndromes, the seizures resolve over time; in others, the seizure disorder may be stationary for prolonged periods, or herald the onset of even more frequent seizures, progressive neurologic deficits, or death.

  • Molecular mechanisms and the affected neuronal circuits differ broadly among defined seizure types and between epilepsy syndromes. Numerous gene loci have now been identified for some common seizure patterns and syndromes, many of which are recognized to comprise multiple, genetically distinct diseases. These findings indicate that inherited epilepsies reflect a large and diverse group of rare genetic disorders.

  • Genes for epileptogenesis include a broad range of molecules regulating brain assembly, activity, and cell death. The underlying human epilepsy syndromes discovered to date can be provisionally divided into three broad categories. The first category includes developmental cortical malformations and cellular migration disturbances leading to early structural changes in neural connectivity. The second category consists of dynamic excitability defects in neuronal ion channels, receptors, and the regulation of synaptic transmission. The third category comprises errors of cellular homeostasis and intermediary metabolism leading to oxidative deficiency, aberrant proteolysis, and neurodegeneration. Spontaneous mutations and targeted mutagenesis in experimental models reveal an even more extensive array of genes associated with epilepsy that affect synaptogenesis, vesicle release, and neuroplasticity.

  • Epilepsy genes, despite their remarkable functional diversity, represent a specific subgroup of neurogenetic disorders, because many inherited defects in the biology of neurons or glia do not lead to a seizure phenotype. Those that are not permissive for spontaneous epilepsy may lower the threshold for seizures triggered by various stimuli or other mutant alleles. Genomic comparisons of tissue from identified monogenic epilepsies with multigenic and acquired syndromes may ultimately reveal the critical molecular neuropathology required for an ...

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