부산대학교 도서관

The cost of epilepsy to an individual lies not just in the burden of having recurrent seizures but also in the condition's neurodevelopmental, cognitive, psychological and social co-morbidities. Presently, our understanding of the pathophysiological mechanisms underlying epilepsy and its neurocognitive co-morbidities remains severely limited, translating to our current lack of targeted treatment options. This PhD study aims to better understand the pathophysiological mechanisms underlying epilepsy and its neurocognitive co-morbidities through the clinical and molecular genetic study of a cohort of patients with Landau Kleffner syndrome (LKS), an epilepsy syndrome characterised by seizures, and neurodevelopmental regression in the form of loss of speech and language skills. Patients were recruited from a database of children referred for LKS at Great Ormond Street Hospital's Developmental Epilepsy Clinic. Clinical data was extracted through case note review. As mutations in GRIN2A, a gene encoding the N2A subunit of the Nmethyl-D-Aspartate (NMDA) receptor have previously been described in 8-20% of individuals with LKS and related disorders, recruited individuals were screened for GRIN2A mutations via Sanger Sequencing and multiplex-ligation probe amplification. Functional investigations exploring gene/protein expression, protein localisation and channel function were carried out on missense GRIN2A mutations identified. Individuals who screened negative for GRIN2A variants underwent whole exome sequencing or whole genome sequencing to identify novel genes associated with LKS. This study has drawn conclusions that LKS is a neurodevelopmental disorder and clinical features influencing prognosis include age at onset of regression, non-verbal intelligence, and the presence of motor difficulties. GRIN2A mutations are likely to lead to LKS through overall NMDA receptor loss of function effects. Nonetheless, LKS may be a complex disorder with multi-factorial or oligogenic aetiology. Lastly, the long term potentiation pathway, important for learning and memory mechanisms, features strongly in the pathogenesis of LKS.