Key Points
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Absence seizures are a non-convulsive form of epilepsy that is characterized by a sudden, brief impairment of consciousness. In the electroencephalogram (EEG), absence seizures are accompanied by generalized, synchronous, bilateral spike and slow-wave discharges (SWDs). In childhood absence epilepsy (CAE), the seizures start between 3 and 8 years of age, have a high daily frequency and cannot be induced by sensory stimuli. Most children with CAE show spontaneous remission around adolescence.
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Most of the genetic studies of CAE have failed to identify its genetic basis. Only two mutations have been discovered in people with CAE and additional neurological disorders; these affect the gene GABRG2, which encodes a GABA (γ-aminobutyric acid) receptor subunit, and CACNA1A, which codes for a subtype of Ca2+ channel. Large-scale genome scans have highlighted several susceptibility loci; establishing the importance of these loci to CAE will require identification of the corresponding mutations.
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Spontaneous mutations in mice have resulted in animals that serve as models of absence seizures and ataxia. These mutants, which include tottering, lethargic, stargazer, mocha, slow-wave-epilepsy and ducky, develop SWDs and behavioural arrest. In most cases, the mutation affects a Ca2+ channel subunit. A causative link between these mutations and the SWD phenotype remains to be established.
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In addition to the mouse models, several rat genetic models of absence seizures have been developed. These include the GAERS (genetic absence epilepsy rats from Strasbourg) and the WAG/Rij (Wistar albino Glaxo from Rijswijk) rats. So far, no systematic attempt to identify the genetic basis of the phenotype of these rodents has been undertaken.
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Several clinical and experimental findings have challenged the classical view of SWDs as generalized EEG paroxysms in favour of a 'focal' cortical origin. However, this view does not imply a localized cortical defect, as the lower threshold for the initiation of the discharges could simply reflect a higher sensitivity of the cortex to an abnormality that is expressed in both cortical and subcortical areas.
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From the cellular point of view, the EEG abnormalities that are associated with absence seizures involve mainly thalamic and cortical areas — that is, the thalamocortical loop. Studies in animal models have begun to establish the specific involvement of each cellular element of this loop in the expression of these seizures.
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Genetic and pathophysiological studies in models of absence seizures will help to identify more clearly the mechanisms that underlie SWDs and other electrophysiological abnormalities. Although more stringent classifications of CAE would make it more difficult to select suitable patients for analysis, they could also facilitate the discovery of the genetic traits of CAE.
Abstract
Childhood absence epilepsy is an idiopathic, generalized non-convulsive epilepsy with a multifactorial genetic aetiology. Molecular-genetic analyses of affected human families and experimental models, together with neurobiological investigations, have led to important breakthroughs in the identification of candidate genes and loci, and potential pathophysiological mechanisms for this type of epilepsy. Here, we review these results, and compare the human and experimental phenotypes that have been investigated. Continuing efforts and comparisons of this type will help us to elucidate the multigenetic traits and pathophysiology of this form of generalized epilepsy.
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Acknowledgements
We wish to thank G. Avanzini, D. A. Carter, J. L. Noebels, T. Panayiotopoulos and R. Spreafico for constructive comments, and S. W. Hughes and J. L. Holter for help in the preparation of the manuscript. Our work on absence epilepsy is supported by the Wellcome Trust, the Centre National de la Recherche Scientifique, the Ministère de la Recherche, and the European Union.
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DATABASES
LocusLink
OMIM
generalized epilepsy with febrile seizures plus
idiopathic generalized epilepsies
FURTHER INFORMATION
International League Against Epilepsy
Encyclopedia of Life Sciences
Glossary
- GENERALIZED TONIC–CLONIC SEIZURE
-
A type of seizure that begins with rigidity (tonic phase), followed by repetitive clonic activity of all extremities.
- FEBRILE SEIZURE
-
A generalized seizure that occurs in conjunction with fever.
- PROBAND
-
Usually, the person who serves as the starting point of a genetic study.
- PENETRANCE
-
The proportion of genotypically mutant organisms that show the mutant phenotype. If all genotypically mutant individuals show the mutant phenotype, then the genotype is said to be completely penetrant.
- CONCORDANCE
-
The occurrence of a trait in both of two related individuals, such as twins or siblings.
- GENETIC POLYMORPHISM
-
The simultaneous existence in the same population of two or more genotypes in frequencies that cannot be explained by recurrent mutations.
- NUCLEUS RETICULARIS THALAMI
-
A thalamic nucleus that covers the lateral and anterior aspects of the mammalian thalamus, and almost exclusively contains GABA-producing neurons.
- EPISODIC ATAXIA TYPE 2
-
An autosomal-dominant disorder that is characterized by the recurrence of spells of cerebellar ataxia, usually starting during childhood or adolescence.
- PRAXIS-INDUCED SEIZURE
-
A type of seizure that is induced by performing planned, coordinated movements.
- ICTAL
-
Relating to or occurring during a seizure.
- CENTRENCEPHALIC HYPOTHESIS
-
The idea that generalized SWDs originate in a hypothetical neuronal network — the 'centrencephalon' — that is centred on the upper brainstem and diencephalon, with diffuse cortical projections.
- CORTICO-RETICULAR HYPOTHESIS
-
The idea that generalized SWDs result from an abnormal interaction of ascending inputs from 'midbrain and midline thalamic reticular systems' and a diffusely hyperexcitable coretx.
- LENNOX–GASTAUT SYNDROME
-
A severe form of childhood epilepsy that is characterized by very frequent seizures of several types. Most patients also have severe learning difficulties.
- WEST SYNDROME
-
An epileptic syndrome that is characterized by infantile spasms (generalized seizures), hypsarrhythmia and arrest of psychomotor development at seizure onset.
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Crunelli, V., Leresche, N. Childhood absence epilepsy: Genes, channels, neurons and networks. Nat Rev Neurosci 3, 371–382 (2002). https://doi.org/10.1038/nrn811
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DOI: https://doi.org/10.1038/nrn811
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