Investigation of Voltage-Dependent Calcium Channels as Candidate Genes for Childhood Absence Epilepsy
Abstract number :
1.251
Submission category :
Year :
2000
Submission ID :
2911
Source :
www.aesnet.org
Presentation date :
12/2/2000 12:00:00 AM
Published date :
Dec 1, 2000, 06:00 AM
Authors :
Robert A Robinson, Nichole L Taske, Armin Heils, Michelle Rees, Mark Gardiner, Univ Coll London, London, United Kingdom; Univ fur Epileptologie, Bonn, Germany.
RATIONALE: The aim was to test five voltage-dependent calcium channel genes, CACNA1D, CACNA1E, CACNA1I, CACNA2D2 and CACNG2, as candidates for childhood absence epilepsy (CAE) by linkage analysis. METHODS: Nineteen multiplex nuclear families with a proband with CAE were ascertained. This resource includes 93 individuals with 49 affecteds. Diagnostic criteria were absence seizures (of any type except myoclonic absences) with onset between 2 and 12 years and an ictal EEG showing bilateral, synchronous, symmetrical discharges of 2.5-4 Hz spike-wave or polyspike-wave complexes on a normal background. Two polymorphic microsatellite markers spanning CACNA1E on 1q31-32, five spanning CACNA2D2 and CACNA1D on 3p14-21 and four spanning CACNG2 and CACNA1I on 22q12-13 were typed. Power was calculated by SLINK. Parametric linkage analysis was carried out using GENEHUNTER, assuming autosomal dominant (AD) or autosomal recessive (AR) inheritance and 70% penetrance. RESULTS: The simulated average maximum pairwise LOD scores were 3.44 (AD) and 1.80 (AR). Multipoint analysis using the markers spanning CACNA2D2 and CACNA1D gave a maximum lod score of 1.45 between D3S1289 and D3S1300 assuming AR inheritance. The markers spanning CACNG2 and CACNA1I gave negative lod scores of < -3.8 (AD) and < -14.3 (AR). In the 6.5cM interval between D1S212 and D1S2848 that encompasses CACNA1E, negative lod scores of < -4.6 (AR) and -0.4 to -5.7 (AD) were obtained. CONCLUSIONS: Voltage-dependent calcium channels are a strong class of candidate gene for CAE. They are critical for generation of the 3Hz spike-wave discharges associated with absence seizures, are blocked by anti-absence epilepsy drugs, and are mutated in mouse models of spike-wave epilepsy. These results provide suggestive evidence for a susceptibility locus on 3p14-21 in the region encompassing CACNA2D2 and CACNA1D. Assuming locus homogeneity, these results also exclude three other voltage dependent calcium channel genes from a major contribution to the CAE phenotype. This work was supported by The Wellome Trust, The Medical Research Council and Action Research.