Genotype phenotype relationships in SCN1A related childhood epilepsies

Most mutations in SCN1A-related epilepsies are novel and when an infant presents with febrile seizures (FS) it is uncertain if they will have simple FS, FS+ or develop a severe epilepsy such as Dravet Syndrome. The main aim of this work has been to translate specific genetic findings in SCN1A related epilepsies not only to the phenotype, but to examine the implications this has on treatment and quality of life in children and their families. Clinical and genetic data were collected from 273 individuals with SCN1A mutations identified in our laboratory between November 2005 and February 2010. I examined whether the mutation class, distribution or nature of amino acid substitution correlated with the epilepsy phenotype, using the Grantham Score (GS) as a measure of physicochemical difference between amino acids. From structured referral data I analysed a range of clinical characteristics including epilepsy phenotype, seizure precipitants, EEG data, imaging studies, mutation class and response to medication and determined predictors of developmental outcome. I developed novel ideas on how to characterise mutations in SCN1A related epilepsies, showing that phenotypes are not determined by chance, but are in part determined by defined physico-chemical changes affecting a specific location in the protein structure. I was able to demonstrate that these principles not only apply to the SCN1A gene but also to the wider voltage gated sodium channel family and related diseases. This study has been the largest to date to systematically examine the prognostic, clinical and demographic features of Dravet syndrome. The overall incidence of Dravet syndrome was found to be at least one in every 28,600 UK births. Clinical features predicting a worse developmental outcome included status epilepticus, interictal EEG abnormalities in the first year of life and a motor disorder. No significant effect was seen for seizure precipitants, MRI abnormalities or mutation class (truncating vs. missense). Sodium valproate, benzodiazepines and topiramate were reported the most helpful medications and aggravation of seizures was reported for carbamazepine and lamotrigine. Health related quality of life (HRQOL) has emerged as a widely accepted measure to evaluate how chronic disease impacts on an individual’s well-being and I examined in detail the comorbidities and predictors of health related quality of life in Dravet syndrome. HRQOL was evaluated with two epilepsy-specific instruments, the Impact of Pediatric Epilepsy Scale (IPES) and the Epilepsy & Learning Disabilities Quality of Life Questionnaire (ELDQOL), a generic HRQOL instrument the Pediatric Quality of Life Inventory (PedsQL) and a behavioural screening tool, the Strength and Difficulties Questionnaire (SDQ). 163 individuals with Dravet syndrome and their families participated in the questionnaire study. HRQOL was significantly lower for children with Dravet syndrome compared to normative data. One third of children had conduct problems and two thirds had hyperactive or inattentive behaviour. Regression analysis revealed that behavioural problems were the strongest predictors of poorer HRQOL. Identification of specific comorbidities will help us to better recognise and understand the needs of children and families with Dravet syndrome and facilitate a distinct multi-disciplinary approach to management. Genetic testing in the epilepsies has become an increasingly accessible clinical tool and this is the first study to assess the impact of SCN1A testing on patient management from both carer and physician perspectives. The vast majority of parents whose children tested positive for a mutation reported genetic testing helpful, leading to treatment changes resulting in fewer seizures, and improved access to therapies and respite care. Nearly half of the physicians reported that a positive test facilitated diagnosis earlier than with clinical and EEG data alone. In two thirds it prevented additional investigations and altered the treatment approach; it influenced medication choice in three quarters of cases and through medication change improved seizure control in forty percent. In addition to confirming a clinical diagnosis, a positive SCN1A test enabled early diagnosis, influenced treatment choice and facilitated improvements in clinical management, especially in the very young. Finally I hope that this work will contribute to a better understanding of the causes of SCN1A related epilepsies. Furthermore I hope that it will provide evidence to aid earlier diagnosis and treatment of children with severe infantile epilepsies and that it will offer more information for genetic counselling. These improvements in epilepsy care and seizure control could help prevent or reduce the disability associated with SCN1A related epilepsies such as learning and behaviour problems and would improve the quality of life for children and families