Genetic Architecture of Idiopathic Generalized Epilepsy: Clinical Genetic Analysis of 55 Multiplex Families

Abstract

Summary:Purpose: In families with idiopathic generalized epilepsy (IGE), multiple IGE subsyndromes may occur. We performed a genetic study of IGE families to clarify the genetic relation of the IGE subsyndromes and to improve understanding of the mode(s) of inheritance.Methods: Clinical and genealogic data were obtained on probands with IGE and family members with a history of seizures. Families were grouped according to the probands' IGE subsyndrome: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with tonic-clonic seizures only (IGE-TCS). The subsyndromes in the relatives were analyzed. Mutations in genes encoding α1 and γ 2 γ -aminobutyric acid (GABA)-receptor subunits, α1 and β1 sodium channel subunits, and the chloride channel CLC-2 were sought.Results: Fifty-five families were studied. 122 (13%) of 937 first-and second-degree relatives had seizures. Phenotypic concordance within families of CAE and JME probands was 28 and 27%, respectively. JAE and IGE-TCS families had a much lower concordance (10 and 13%), and in the JAE group, 31% of relatives had CAE. JME was rare among affected relatives of CAE and JAE probands and vice versa. Mothers were more frequently affected than fathers. No GABA-receptor or sodium or chloride channel gene mutations were identified. Conclusions:The clinical genetic analysis of this set of families suggests that CAE and JAE share a close genetic relation, whereas JME is a more distinct entity. Febrile seizures and epilepsy with unclassified tonic-clonic seizures were frequent in affected relatives of all IGE individuals, perhaps representing a nonspecific susceptibility to seizures. A maternal effect also was seen. Our findings are consistent with an oligogenic model of inheritance. Key Words: Genetics-Idiopathic generalized epilepsy-Family studies.Idiopathic generalized epilepsies (IGEs) are the most common types of epilepsy in childhood and adolescence. Based on the main seizure type and age at onset, four classic subsyndromes exist: childhood absence epilepsy (CAE), juvenile absence epilepsy (JAE), juvenile myoclonic epilepsy (JME), and IGE with tonic-clonic seizures ( Although in rare families, autosomal dominant inheritance occurs (6), clinical genetic data indicate that in the majority of families, a single-gene mode of inheritance is implausible, and complex inheritance involving two or more genes is likely (3)(4)(5)7,8).Studies of families with IGEs show that 5 to 10% of first-degree relatives have seizures but with phenotypic heterogeneity (7,9-11). Two centers have analyzed the IGE subsyndromic patterns in large numbers of families. An Italian study of the families of 46 probands with IGE, excluding JAE, showed that 24% relatives of CAE probands and 44% relatives of JME probands were 467

Besondere bildgebende Befunde bei primär generalisierten Epilepsien

“…Den idiopathisch generalisierten Epilepsien (IGE) liegt eine genetisch determinierte neuronale Entwicklungsstörung zugrunde [8,11,16]und üblicherweise ist die konventionelle klinische Magnetresonanztomographie(MRT)-Bildgebung bei IGE-Patienten unauffällig. Allerdings haben Gruppenanalysen schon sehr früh diskrete strukturelle Auffälligkeiten bei IGE gezeigt.…”

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Den idiopathisch generalisierten Epilepsien (IGE) liegt eine genetisch determinierte neuronale Entwicklungsstörung zugrunde [8,11,16]

Funktionelle MRT-Befunde bei der JMEVor einigen Jahren ergänzten funktionelle MRT(fMRT)-Untersuchungen diese Befunde und zeigten bei JME-Patienten eine belastungsabhängige Koaktivierung des motorischen Kortex bei kognitiver Anstrengung und eine erhöhte funktionelle Konnektivität zwischen präfron-talen kognitiven Arealen und dem motorischen System (. Abb.

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“…Den idiopathisch generalisierten Epilepsien (IGE) liegt eine genetisch determinierte neuronale Entwicklungsstörung zugrunde [8,11,16] …”

Genetic Epidemiology of Epilepsy or What Do We Tell Families?

“…Similarly, in data from the Epilepsy Family Study of Columbia University (EFSCU), the increased risk for epilepsy in parents and siblings of probands with idiopathic epilepsy was not restricted to the same type of epilepsy as in the proband (13). Different IGE syndromes have been frequently found to occur within the same family, and it is suspected that this may result from several genes acting together, some that increase risk for IGEs overall, and others more specific for seizure type (20,22,23). Overall, it appears that some genetic influences raise risk for idiopathic epilepsy regardless of type, while others, which may operate simultaneously, raise risk for specific seizure or syndrome types.…”

Genetic Epilepsy Syndromes Without Structural Brain Abnormalities: Clinical Features and Experimental Models

“…An underlying genetic defect has been clearly demonstrated for some forms with Mendelian inheritance [3]. In particular, genetic studies of families and twins contributed to the definition of genetic epilepsy, and especially to the evaluation of the risk of familial recurrence [4,5]. After the first report in 1988 of the chromosomal mapping of juvenile myoclonic epilepsy [6], several additional loci were demonstrated to be implicated in syndromic epilepsies.…”