Abstracts

Rationale: Most mutations in the SCN1A gene associated with epilepsy are novel and how they relate to the phenotype and quality of life of that individual and whether genetic knowledge will alter management is uncertain. We characterised SCN1A mutations based on mutation class and physico-chemical properties and related this to clinical symptoms and parent rated severity of epilepsy and quality of life measures. Parent and physicians experiences of genetic testing were assessed to ascertain if testing resulted in management change. Methods: We reviewed clinical referral and genetic data on 268 individuals with SCN1A mutations identified in our centre. Mutations were classified as mild/moderate if they were missense with a physico-chemical property difference in amino acids (Grantham score - GS) ? 100, and severe if they were truncating or missense with GS > 100. Parents and physicians completed questionnaires on the role of genetic testing. Parents completed the Paediatric Quality of Life Inventory, Impact of Paediatric Epilepsy Scale, and Epilepsy and Learning Disabilities Quality of Life Questionnaire. Results: 94 individuals (35%) had a mild/moderate SCN1A mutation and 174 individuals (65%) a severe mutation. In comparison to a mild/moderate mutation, a severe mutation was associated with earlier disease onset (6 vs 8 months; p < 0.001), more frequent myoclonic seizures (71% vs 57%; X² = 5.0; df = 1; p = 0.025), more frequent acquired movement disorder (47% vs 28%; X² = 6.5; df = 1; p = 0.010) and worse developmental outcome (X² = 13.1; df = 4; p = 0.011). 135 parents and 101 physicians of mutation positive patients returned postal questionnaires. Severe mutations were associated with overall poorer rated quality of life (p = 0.007), more severely rated epilepsy (p = 0.001), worse rated language ability (p = 0.020), worse rated school and learning performance (0.039) and lower health related quality of life for physical (p = 0.030) and daily tasks (p = 0.014). In 117/135 of cases (87%) parents reported genetic testing was helpful. In 73/135 (54%) it led to a change in treatment (80% introduction of new medication, 20% stopping medication). Treatment change improved seizure control in 55% and reportedly had a positive effect on development in 27%. In 45/101 of cases physicians reported that genetic testing allowed them to make an earlier diagnosis than on clinical criteria alone. In 47% of cases it helped prevent misdiagnosis and in 70% the child was saved additional investigations. Genetic data influenced choice of medication in 72% of cases and changes consequent upon testing resulted in improved seizure control in 33%. Conclusions: SCN1A genetic testing can result in management changes in children with epilepsy. Truncating mutations and missense mutations with a high Grantham score are more likely to be associated with a poorer quality of life, poorer cognitive abilities and worse seizure control. Parents and physicians have similar perspectives on the role of SCN1A testing.