Genetic architecture of idiopathic generalized epilepsy: clinical genetic analysis of 55 multiplex families.
OBJECTIVE
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 alpha1 and gamma 2 gamma-aminobutyric acid (GABA)-receptor subunits, alpha1 and beta1 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.
Marini
Carla
C
Epilepsy Research Institute, Department of Medicine (Neurology) The University of Melbourne, Austin Health, Victoria, Australia.
Scheffer
Ingrid E
IE
Crossland
Kathryn M
KM
Grinton
Bronwyn E
BE
Phillips
Fiona L
FL
McMahon
Jacinta M
JM
Turner
Samantha J
SJ
Dean
Joanne T
JT
Kivity
Sara
S
Mazarib
Aziz
A
Neufeld
Miriam Y
MY
Korczyn
Amos D
AD
Harkin
Louise A
LA
Dibbens
Leanne M
LM
Wallace
Robyn H
RH
Mulley
John C
JC
Berkovic
Samuel F
SF
D000293:Adolescent; D000328:Adult; D002648:Child; D018118:Chloride Channels / Q000235:genetics; D004832:Epilepsy, Absence / Q000235:genetics; D004829:Epilepsy, Generalized / Q000235:genetics*; D005190:Family; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D018740:Genetic Heterogeneity; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D020190:Myoclonic Epilepsy, Juvenile / Q000235:genetics; D010375:Pedigree; D010641:Phenotype; D018079:Receptors, GABA / Q000235:genetics; D015222:Sodium Channels / Q000235:genetics
D018118:Chloride Channels; D018079:Receptors, GABA; D015222:Sodium Channels