We identified two large French-Canadian (FC) pedigrees with idiopathic partial epilepsy. Family studies of over 500 members from these two families revealed over 63 individuals reported to have seizures or seizure-like histories. Pedigree analysis confirmed an autosomal dominant inheritance with reduced penetrance. Most of the affected individuals shared a number of clinical characteristics compatible with the definition of a novel genetic form of epilepsy syndrome. We termed it as familial partial epilepsy with variable foci (FPEVF), which was recently described by Scheffer et al. (1998) in one Australian family with eight possibly affected individuals. The most prominent clinical feature of FPEVF is the presence of variable seizure foci in different affected individuals within the same family. Most affected individuals in the two FC families present infrequent, brief, non-clustering, nocturnal, partial seizures. Age of onset is between 5 and 25 years. Affected individuals are neurologically intact without any detectable pathological lesion(s). / These two families were then subjected to a full-scale molecular genetic study. No linkage to any known loci for idiopathic partial epilepsy was detected, including the suggested chromosome (Chr) 2q locus for FPEVF in the Australian FPEVF family, the Chr 20q13.2 and 15q24 loci for autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) and the Chr 10q locus for autosomal dominant temporal lobe epilepsy with auditory symptoms (ADTLEAS). Significant linkage (LOD score = 8.60) was detected with markers on Chr 22 q12 during a genome scan. Collaborating with a group from Australia, we confirmed another two FC families and two non-FC families with compatible linkage to the same locus and a cumulative LOD score of 14.79 with marker D22S689. The minimum candidate region of FPEVF has been finally defined to an interval of 3.8 cM between markers D22S 1163 and D22S 1686 on Chr 22q12. We proceeded to search for the gene mutation by directly sequencing the coding regions of all candidate genes within the FPEVF region, an interval of 5.04 Mb harboring approximately 100 known or predicted genes. So far, 77 candidate genes have been sequenced, and no mutation has yet been found. Since there is no known ion channel gene mapped to this region, FPEVF is probably the first non-ion channel gene causing human idiopathic epilepsy*. / *After submission of this thesis for examination, Kalachikov et al. (2002) identified LGI1 (leucine-rich gene, glioma inactivated), a possible tumor suppressor, as the gene for ADTLEAS. This is the first evidence for a non-ion channel gene causing idiopathic epilepsy in humans.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:QMM.38440 |
| Date | January 2001 |
| Creators | Xiong, Lan, 1966- |
| Contributors | Andermann, Eva (advisor), Pandolfo, Massimo (advisor) |
| Publisher | McGill University |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Format | application/pdf |
| Coverage | Doctor of Philosophy (Division of Neuroscience.) |
| Rights | All items in eScholarship@McGill are protected by copyright with all rights reserved unless otherwise indicated. |
| Relation | alephsysno: 001864336, proquestno: NQ78801, Theses scanned by UMI/ProQuest. |
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