Childhood Absence Epilepsy
An epidemiological, neuropsychological & molecular genetic study
Acta Universitatis Tamperensis No. 1597

By Auli Siren
May 2011
Tampere University Press
Distributed by Coronet Books
ISBN: 9789546425768
89 pages
$82.50 Paper original

Childhood absence epilepsy (CAE) is a well known syndrome belonging to the group of idiopathic generalised epilepsies (IGE). CAE is considered as a benign epilepsy syndrome with respect to seizure remission and cognitive functions. The genetic etiology of CAE has been under research without conclusive answers. This study was carried out to evaluate the short-term neurocognitive outcome and short- and long-term clinical outcome in patients with CAE and to identify the clinical features and molecular genetic background in two families with CAE and febrile seizure (FS) as main phenotypes. In the short-term clinical and neurocognitive outcome study (Study 1), eleven patients with typical absence seizures were studied at the time of the diagnosis and after ten months’ antiepileptic drug (AED) treatment by video- electroenchephalography (video-EEG) recordings, general intelligence (IQ) measurements and computerized neurocognitive assessments focusing on the fine-motor fluency, sustained attention and visual and spatial memory.

Eleven age and gender matched control individuals were studied accordingly. The long-term clinical outcome of patients with CAE is based on the data of Studies 1, 2 and 4. The patients and/or their parents were interviewed and the medical files were reviewed to collect data on the course of the disease, medication, side-effects of AED, remission and family history. In Studies 3 and 4, members of two families (family 98 and family 5) with a proband diagnosed with CAE and other family members with epilepsy or FS participated in the clinical and molecular genetic studies. The following epilepsy syndromes or seizure types were presented in these families: CAE (4), CAE and FS (1), FS only (9), benign temporal lobe epilepsy (2), Panayiotopoulos syndrome (PS) (1), probable PS and FS (1) and FS and secondary generalised epilepsy (1). In both families a genome wide scan (GWS) with fine-mapping of the candidate loci and sequencing of the candidate genes were performed. In the short-term outcome study (Study 1) the patient group improved in fine-motor fluency, attention and visual memory whereas the control group improved in fine-motor fluency and attention. The impairment in visual memory in the patient group correlated with the duration of the generalised discharges in their EEG recordings and improved significantly as a result to seizure cessation. In the long-term outcome study (Study 2) the mean follow-up time was 10 years (range 2-22 years). Ninety-four percent of the patients had been seizure free for more than 2 years. Thirty- six percent of the patients with CAE had relatives with epilepsy or FS.

All together sixty-one family members of families 98 and 5 participated in the clinical and molecular genetic study in Studies 3 and 4. In family 98 an autosomal dominant inheritance of seizure susceptibility with a contribution of three chromosomal loci, including a probable new locus on chromosome 17q12-24 and two modifier loci on chromosomes 5q11.2 and on 18p11- q11 were identified. Ten brain-expressed ion-channel genes were sequenced. No disease-associated alteration was found. In family 5, the inheritance pattern was suggestive of a polygenic complex inheritance. Two loci on chromosomes 16p12.3-p13.3 and 22q13.1-q13.31 were fine-mapped. After fine-mapping using multipoint non-parametric analysis, a p-value of 0.0014 was obtained between the disease and marker D16S3072 at chromosome 16p13.3. Sequence analysis of voltage-dependent T-type calcium channel alpha 1H subunit (CACNA1H) on chromosome16p13.3 revealed a novel sequence alteration resulting in the p.Pro686Leu amino acid change. This variant partially segregated with the affection status in the family. This study demonstrates that most patients with CAE reached seizure freedom and especially visual memory improves after seizure cessation. About a third of the CAE patients had relatives with epilepsy or FS. Clinical and molecular genetic results in two families with heterogenous phenotypes including CAE complied with the complex genetics model of common epilepsies.

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