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Trial Lecture – time and place
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Adjudication committee
- First opponent: Professor Annapurna Poduri, Harvard Medical School, United States
- Second opponent: Professor Martin Zenker, Otto-von-Guericke University Magdeburg, Germany
- Third member and chair of the evaluation committee: Professor II Angelika Sorteberg, University of Oslo
Chair of the Defence
Associate Professor Rune Enger, University of Oslo
Principal Supervisor
Researcher Kaja Kristine Selmer, OUS - Oslo University Hospital
Summary
Epilepsy is a common neurological disorder that affects up 1% of the population. About one third of epilepsy patients do not achieve seizure freedom, and the condition may result in considerable loss of life quality and premature mortality. There has been little change in the proportion of patients not achieving seizure freedom, despite the development of numerous antiseizure medications over the last decades. Numerous pathological processes may result in epilepsy, and it is crucial to understand these better in order to device better diagnostics and treatments against the epilepsies.
In the course of this PhD project, ten families with epilepsy of unknown etiology were studied, as well as six unrelated patients with Sturge-Weber syndrome. In this thesis, the genetic cause and pathogenesis was explored with whole exome sequencing and cell-biologic techniques. In Sturge-Weber syndrome, most patients have a port-wine colored birthmark and thickened, tortuous blood vessels in their brain and/or eye. These changes frequently lead to epilepsy, migraine and glaucoma. Six patients were recruited, and skin biopsies were taken from their birthmark and healthy skin. Ultra-deep sequencing revealed that five participants had a known somatic mutation in the GNAQ-gene, that was only present in birthmark biopsies. The sixth patient had a somatic mutation in a biologically related gene, GNB2. By comparing the molecular effects of these two somatic variants, we found that they had very different effects on the MAPK pathway, which thus is unlikely to be the main downstream pathological mechanism in Sturge-Weber syndrome. Similar effects on the YAP-pathway may implicate it as more central in the pathogenesis of the syndrome.
Two brothers with a progressive myoclonus epilepsy were by whole exome sequencing found to share homozygous variants in KCTD7. Further functional studies revealed that this and other known pathogenic variants in the gene caused reduced potassium currents across cell membranes, damaged glutamine into neurons and loss of membrane localization. Two sisters with epilepsy and brain calcifications underwent whole exome sequencing. Both shared a heterozygous variant in SLC20A2, associated with primary familial brain calcifications, and a variant in CHRNB2, a gene associated with frontal lobe epilepsy. Rates of epilepsy among people with PFBC are low, raising the possibility of that a “second hit” is necessary to cause epilepsy in these patients.
In summary, this research has contributed to an increased understanding of epilepsy as part of the phenotype of PFBC, the pathological mechanisms for KCTD7-related progressive myoclonic epilepsy and Sturge-Weber syndrome, where it has also uncovered a previously unknown gene that causes the disorder.
Additional information
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