Medicine (Austin & Northern Health) - Theses
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ItemFamily studies of epilepsy with simple and complex inheritance( 2002)The epilepsies are a group of disorders where genetic factors have been long known to play an important role. Genetic research in the last decade has led to the discovery of several mutated genes in some uncommon human epilepsies with autosomal dominant inheritance. The search of genes for epilepsies with complex inheritance has however been less successful. The general aim of this thesis was to study the genetics of epilepsies with simple and complex inheritance, using families with multiple affected family members. Accurate phenotyping was a strategy I used to try and minimise the problem of genetic heterogeneity. The study involved a long interview with all available living family members to collect clinical and genealogical information. Detailed electro-clinical characterisation of each individual's epilepsy syndrome was obtained. Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) was studied as a prototype of simple inheritance. Detailed clinical analysis of 5 ADNFLE families revealed some new clinical features including seizures triggered by sound or movement, and precipitated by fever, extreme tiredness or stress. In order to help distinguishing NFLE from parasomnias, I developed a motor activity scoring system in sleep (MAISS). In most cases this confirmed the clinical and or electrographic diagnosis. Molecular genetic analysis of 5 families and 11 sporadic cases by our collaborators revealed 2 new mutations in the genes coding for α4 and β2 subunits of the acetylcholine receptors (CHRNA4 and CHRNB2). A de novo CHRNA4 mutation was found in the proband and her second son in family A. This is the first de novo mutation found in epilepsy suggesting also that sporadic cases could have a genetic aetiology and such patients should be tested for the known mutations. A new mutation in CHRNB2 was found in family B, the mutation was present in family members with ADNFLE but was not found in family members with parasomnias defined by their MAISS score. The finding does not support the hypothesis of a common genetic aetiology between ADNFLE and parasomnias. Idiopathic generalized epilepsies (IGEs) are the most common and important group of epilepsies with complex inheritance. An exceptionally large family with 35 affected individuals was studied. The phenotypes included childhood absence epilepsy (CAE), febrile seizures (FS) and generalized epilepsy with febrile seizures plus (GEFS+). Molecular genetic analysis showed that affected individuals had a mutation in the gene coding for the γ2 subunit of the GABAA receptor (GABRG2). The structure of the pedigree suggested that, in this family FS were inherited in an autosomal dominant fashion and caused by GABRG2 mutation. However, clinical genetic analysis suggested that whilst this mutation contributed to the CAE and GEFS+ phenotypes, it was likely that other genes were also involved. A second linkage analysis inclusive of only subjects with CAE disclosed a number of putative loci that could contain genes contributing to the absence epilepsy phenotype. I also studied 55 small families with IGEs that were more representative of IGEs found in the community. The clinical genetic analysis of the families showed a relatively homogeneous pattern of syndrome distribution within families. The phenotypic concordance with the proband was higher in first degree relatives compared to more distant relatives. The family analysis showed that the two recognized absence epilepsy syndromes were genetically closely related whilst juvenile myoclonic epilepsy was more distinct. The GABRG2 mutation was not found in any of these families. Two families with biparental IGEs were studied. The affected offspring of the 2 families had epilepsy phenotypes with characteristics of both parents' epilepsies. Finally, of 121 consecutive patients with new-onset IGE, 28% had seizures beginning at age 20 years or later (adult-onset). Similar to the classical IGE with age of onset before 20 years (as described by the ILAE classification), patients with adult-onset IGE could also be divided in subgroups depending on the predominant seizure types including absences, tonic-clonic and myoclonic seizures. Pedigree analysis of the 121 IGE patients and the comparison of the proportion of affected relatives between classical and adult-onset IGEs patients suggested a predominant genetic aetiology in both. In some pedigrees classical and late-onset IGEs patients co-occurred suggesting that they might share genetic determinants. Therefore adult-onset IGEs should be included in studies were genes for IGEs are sought. In conclusion the data from the large family in which a GABRG2 mutation was found, from the small multiplex families including biparental families and from patients with adult-onset IGEs all underscore the genetic basis of IGEs. Moreover, the clinical analyses, with distinct identifiable subsyndromes, is more suggestive of an oligogenic model of inheritance, involving few genes, rather than a polygenic model where many genes of small effect contribute to the individual phenotype.