ABSTRACT

The PhD dissertation is based on four studies carried out at the Department of Neurology, Odense University Hospital, and the Danish Twin Registry, University of Southern Denmark.

Epilepsy is one of the most common chronic neurological diseases affecting approx. 1% of the population. Febrile seizures (FS) affect 2 to 5% of children, and are the most common seizure disorder in childhood. Epilepsy is a heterogeneous disorder covering more than 40 phenotypes, and both epilepsy and FS often run in families. Aggregation of a disease in a family can be caused by shared genes or shared environment.

The aims of the dissertation were: 1) to study the relative contribution of genetic and environmental factors in the aetiology of FS and epilepsy in general and in the major epilepsy syndromes using data from almost 35,000 Danish twins, and 2) to establish an international collaboration for future studies on genetics of seizures and epilepsy. Classical twin studies and biometrical analyses were conducted in Danish twins on self-reported epilepsy (N=11,900 pairs), on self-reported FS (N=11,872 pairs), on neurologist-verified and classified epilepsy data, (N=214 pairs with seizures, N=190 pairs with epilepsy), and on self-reported epilepsy, FS, other seizures and staring spells from three twin populations (US, Norwegian and Danish twins, N=47,626 twin pairs).

All Danish twin pairs reporting a history of epilepsy underwent a detailed interview concerning seizure history. Medical records were obtained from hospitals and treating doctors. This Information was used to classify epileptic seizures and epilepsy syndromes according to the classification systems of the ILAE.

Significantly higher probandwise concordance rates were found for monozygotic compared to dizygotic (DZ) twins for febrile seizures and epilepsy overall as well as for both partial and generalized epilepsy. In seizure-concordant twin pairs, 83% of MZ and 65% of DZ pairs had the same major epilepsy syndrome. Analysis of seizure history information combined across Danish, Norwegian and American samples showed significantly higher concordance rates for MZ compared to DZ twins for epilepsy, FS, other seizures and staring spells. Based on the Danish data a heritability of 70%-88% was found for epilepsy and 70% for FS.

These studies have demonstrated a substantial impact of genetic factors in the aetiology of epilepsy and FS. The finding of a higher phenotypic similarity in seizure concordant MZ pairs compared to DZ pairs suggests that syndrome specific genes may exist.

The merger of data collected from twin populations in Denmark, Norway and the US has resulted in the largest unselected, population-based sample of twins with seizures to be established to date. This sample will be an important resource for future genetic studies of epilepsy and FS.