This thesis discusses four studies, looking for genetic determinants of common epilepsies: 1) A genome-wide association study (GWAS) of partial epilepsies (PE), which was the first published GWAS in the field of epilepsy (Chapter 4). 2) A GWAS of mesial temporal lobe epilepsy (MTLE) with hippocampal sclerosis (HS) (Chapter 5). 3) A case series of patients with refractory MTLE, operated and found to have large microdeletions at 16p13.11, 15q11.2 and others (Chapter 6). 4) A clinical, genetic and neuropathologic study of a series of patients with Dravet syndrome (DS), diagnosed as adults, including genotype-phenotype correlation analysis (Chapter 7). The main findings include: 1) The GWAS of PE has not yielded any genome-wide significant association with common genetic variants, possibly because of insufficient power and phenotypical heterogeneity. It is, however, a strong foundation for further studies, illustrating the feasibility of large multicentre GWAS in the epilepsies (Chapter 4). 2) The GWAS of MTLEHS yielded a borderline genome-wide statistically significant association with three common genetic variants close or intronic to the SCN1A gene, especially in MTLEHS with antecedents of childhood febrile seizures (Chapter 5). 3) Large microdeletions at 16p13.11 and others were found in patients with MTLEHS and not only in idiopathic non-lesional epilepsies. Good outcome after resective epilepsy surgery is possible in “typical” MTLEHS even with large microdeletions (Chapter 6). 4) The identification of a cohort of adults with DS, not diagnosed as children, allowed the description of long-term evolution through adulthood and recognition of clinical features shared later in the evolution. Over sixty percent had SCN1A mutations. Missense mutations were more frequent in patients who survived through adulthood, with truncating mutations and large deletions only found in those who died in early childhood. Medication changes after diagnosis led in some cases to better seizure control, cognition and quality of life. Further evidence for DS as encephalopathy came from post mortem histopathology, with no neuronal loss found in cerebral cortex or hippocampus.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:626776 |
| Date | January 2014 |
| Creators | Catarino, C. B. |
| Publisher | University College London (University of London) |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://discovery.ucl.ac.uk/1418934/ |
Page generated in 0.0013 seconds