Childhood Absence Epilepsy Due to an Interaction of a GABA Receptor Gene Mutation and a Putative Second Locus on Chromosome 13.
Abstract number :
E.08
Submission category :
Year :
2001
Submission ID :
1663
Source :
www.aesnet.org
Presentation date :
12/1/2001 12:00:00 AM
Published date :
Dec 1, 2001, 06:00 AM
Authors :
C. Marini, MD, Epilepsy Research Institute, University of Melbourne, Melbourne, Victoria, Australia; R.H. Wallace, PhD, Centre for Medical Genetics, Women[ssquote]s and Children[ssquote]s Hospital, Adelaide, South Australia, Australia; L. Harkin, MSc, Cen
RATIONALE: We recently identified a functionally significant mutation in the gamma2 subunit gene of the GABA-A receptor in a large family with childhood absence epilepsy (CAE) and febrile seizures (FS). CAE, a common idiopathic generalized epilepsy (IGE), is determined by more than one gene. We recently developed a digenic hypothesis for idiopathic generalized epilepsies (IGEs). Here we attempt to identify a second locus using linkage analysis based on detailed phenotypic analysis of the pedigree.
METHODS: We performed interviews in all available members using a validated questionnaire, neurological examination and EEG. A detailed pedigree was constructed and blood samples were collected on consenting individuals. Linkage analysis for a putative second gene was performed including only subjects with CAE.
RESULTS: We interviewed 220 family members and 35 had seizures. We were able to define the epilepsy phenotype of 30 individuals: typical CAE (8 individuals), FS alone (15), febrile seizures plus (3), myoclonic-astatic epilepsy (2), generalized epilepsy with generalized tonic-clonic seizures alone (1), partial epilepsy (1). Two patients remained unclassified despite evaluation and for 3 remaining individuals, no information was available. An affected-only analysis incorporating the 8 CAE individuals and obligate carriers failed to reveal a single locus segregating with all cases. However, the highest LOD score was achieved with markers on chromosome 13 and haplotype analysis revealed only a single recombinant.
CONCLUSIONS: Rare large families with a relative high density of specific phenotypes allow us to probe the complex genetics of IGE. Whilst, it is likely that a number of genes contribute to CAE in this pedigree, the data suggest that the locus on chromosome 13 is a strong candidate region. Confirmation of this hypothesis will come from detection of the putative mutant gene, in this and other families.
Support: NHMRC, Melbourne University Scholarship, Bionomics
Disclosure: Salary - Australian Biotechnology company Bionomics provides some salaries; Grant - Bionomics provides research grants to the laboratories; Consulting - Professor Sam Berkovic is on Bionomics Scientific Advisory Board; Stock - Bionomics share options are hel by some authors