Anatomy and Neuroscience - Theses

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    Inherited epilepsy syndromes in multiplex families
    Scheffer, Ingrid Eileen ( 1988)
    The epilepsies are a common group of disorders where genetic factors are known to be important. The challenging search for genes for the idiopathic epilepsies has been difficult and, on commencing this study, no genes for idiopathic epilepsy had been found. The common idiopathic epilepsies, which follow complex (polygenic or multifactorial) inheritance, have been the subject of genetic linkage studies around the world to establish their chromosomal localization. These studies have met with limited and controversial success to date. This may be in part due to the fact that these studies have relied on collections of a number of small families. Such samples are likely to be genetically heterogeneous making linkage analysis difficult. My research has been based on the alternative approach of studying large multiplex families where epilepsy is likely to follow single gene inheritance. This approach has two advantages. First, providing the assumption of a single major gene is correct, the genetic inter-relationships of clinically defined epilepsy syndromes can be determined. Second, large multiplex families with carefully characterized epilepsies are the ideal substrate for molecular genetic analysis to search for epilepsy genes as they are unlikely to be confounded by genetic heterogeneity. I studied many large families with multiple affected individuals (often more than 20) with a history of seizures. This involved study of all available family members, including affected and unaffected individuals, to establish if there was a history of seizures. Detailed electro-clinical characterization of each individual’s epilepsy syndrome was performed using a validated seizure questionnaire, as well as general medical history and neurological examination. Eye witness accounts of seizures were sought as well as previous medical records. Results of investigations such as imaging studies and previous electroencephalographic (EEG) studies were obtained. All available individuals underwent EEG studies, including sleep studies where possible. Genealogical research was carried out where necessary to clarify family relationships for later molecular genetic analysis. My work has resulted in the description of three new autosomal dominant partial epilepsy syndromes expanding the group of idiopathic partial epilepsies, and one new inherited generalized epilepsy syndrome. The most common of the three new partial epilepsies, Autosomal Dominant Nocturnal Frontal Lobe Epilepsy (ADNFLE), is characterized by childhood onset of clusters of violent nocturnal motor seizures. Seizures are often undiagnosed or misdiagnosed as sleep disorders such as nightmares or night terrors, psychiatric diagnoses such as hysteria, or movement disorders. In the largest Australian family where I identified 27 affected individuals, our molecular genetic collaborators (Professor Grant Sutherland, Adelaide) mapped the gene to chromosome 20q13.2. Using a candidate gene approach, together with Dr Ortrud Steinlein (University of Bonn), they identified a mutation in the cx4 subunit of the neuronal nicotinic acetylcholine receptor in this family. This was the first gene described for an idiopathic epilepsy. The second new partial epilepsy syndrome, Autosomal Dominant Rolandic Epilepsy with Speech Dyspraxia (ADRESD), was described in a single Australian family. In this disorder, typical rolandic seizures occur in midchildhood accompanied by centro-temporal spikes on EEG. In this family, epilepsy followed autosomal dominant inheritance and was associated with speech dyspraxia and cognitive impairment. Clinical anticipation was found suggesting the possibility of a triplet repeat expansion as the genetic basis of this disorder. This family may provide a means to finding a gene for the most common epilepsy syndrome of childhood, benign rolandic epilepsy. The third new autosomal dominant partial epilepsy syndrome is Familial Partial Epilepsy with Variable Foci (FPEVF). Also described in a single Australian family, this disorder is intriguing as partial seizures originate in different parts of the cerebral cortex in different family members. In this family, our molecular genetic collaborators have evidence suggestive of linkage to chromosome 2. Febrile Seizures Plus" (GEFS+). Families with GEFS+ are common but have previously escaped classification as many members have mild forms of generalized epilepsy or febrile seizures alone and occasional individuals have severe refractory epilepsies. Penetrance of the disorder is often quite low. GEFS+ is delineated here in a large Victorian family here and subsequently, our Canadian molecular genetic collaborators have found linkage to chromosome 2. The four new inherited epilepsy syndromes described here can be recognized clinically allowing early diagnosis, appropriate management, prognostic and genetic counselling. Clinical characterization has been successful in laying the foundation for molecular genetic research which has resulted in the definite or suggestive genetic linkage in 3 disorders and the discovery of the first genetic defect in an idiopathic epilepsy. Identification of epilepsy genes will yield new insights into the neurobiology of the epilepsies and may lead to targeted anti-epileptic therapies and ultimately prevention of some types of epilepsy.