Focal Epilepsies - Advances in Genetics

 At a time of a virtual explosion in molecular genetics with the advent of whole exome and whole genome sequencing, the genes causing focal epilepsies are being discovered. This symposium will discuss novel findings in the field which are unravelling the aetiology of the non-lesional focal epilepsies.x

LEARNING OBJECTIVES

1. To understand the phenotypic spectrum of genes causing familial focal epilepsy with variable foci including sporadic presentations and small families
2. To understand the different genes contributing to autosomal dominant nocturnal frontal lobe epilepsy and the intellectual and psychiatric co-morbidities that may occur
3. To learn about the genes and mechanisms causing migrating focal seizures of infancy
4. To understand the clinico-molecular approaches to epileptic encephalopathies

LEARNING OBJECTIVES

Familial focal epilepsy with variable foci – a common molecular focal epilepsy
Ingrid Scheffer , Australia

How to approach molecular testing of focal epileptic encephalopathies
Heather Mefford, USA

Migrating focal seizures of infancy, a genetic epileptic encephalopathy
Rima Nabbout, France

Autosomal dominant nocturnal frontal lobe epilepsy – not just a disorder of nicotinic receptors
Shinichi Hirose, Japan
Departments of Pediatrics and Central Research Institute for the Molecular Pathomechanisms of Epilepsy, Fukuoka University, Fukuoka, Japan

Autosomal dominant nocturnal frontal lobe epilepsy (ADNFLE) is familial partial epilepsy characterized by nocturnal motor seizures occurring during sleep and may be misdiagnosed as parasomnia. There is its sporadic form (NFLE). ADNFLE/NFLE may be associated with psychomotor deficits and/or psychiatric features. ADNFLE is the first genetic or idiopathic epilepsy for which the underlying mutation was identified. The first genetic abnormality was found in CHRNA4, the gene encoding the α4 subunit of nicotinic acetylcholine receptors. Mutations were also identified in CHRNA2 and CHRNB2, which encode the α2 and β2 subunits of these receptors, respectively. Mutations in CRH, the gene encoding corticotropin-releasing hormone, have been reported in ADNFLE, albeit rarely. Recently, two new genes have been found to be associated with ADNFLE/NFLE: KCNT1, which encodes a sodium-activated potassium channel, and DEPDC5, which encodes for a molecule associated with mTOR signaling. KCNT1 mutations have been found in cases of ADNFLE/NFLE with severe phenotypes. All the KCNT1 mutations identified so far are missense, gain-of-function mutations. The nature of DEPDC5 mutations remains to be elucidated. We generated transgenic rats bearing a mutation in CHRNA4 and found dysfunction of GABAergic neurons in these rats. Further, attenuation of GABAergic function by furosemide treatment before the onset of seizures prevented epileptogenesis to some extent. We postulate that multiple genetic abnormalities may be involved in a single fundamental pathomechanism, resulting in the relatively uniform phenotype of ADNFLE and NFLE. Interventions to block such putative cascades could provide radical and prophylactic treatments for epilepsy.