Abstracts

Rationale: To date little evidence exists that the nature of a SCN1A mutation in Dravet Syndrome is reflected in the phenotype of that individual. Clinicians referring DNA to our SCN1A gene sequencing service completed a form detailing seizure types, age of seizure onset and developmental outcome. We analysed this data to see whether the mutation type (truncating vs non-truncating) had an impact on the evolution of the phenotype. Methods: Of 186 individuals with a SCN1A mutation detected on sequencing and multiplex ligation probe amplification, 156 had classical Dravet Syndrome (Dravet-C) and 30 were classified as borderline Dravet Syndrome (Dravet-B). We compared the occurrence of different seizure types and their age at seizure onset with results of the mutation analysis. Truncating mutations were defined as nonsense mutations, mutations altering splice sites, small deletions or insertions leading to a frameshift, in-frame deletions and gross or partial rearrangements. All non-truncating mutations were missense mutations. Results: The onset of hemiclonic or focal seizures was reported in 118 individuals. 57 of those had a truncating mutation and 61 a non-truncating mutation. The age of onset for hemi-clonic seizures was significantly lower in individuals with a truncating mutation compared to those with a non-truncating mutation (9 vs 13 months, p < 0.05). Onset of atypical absences was reported in 67 individuals, 35 had a truncating and 32 a non-truncating mutation. Those with truncating mutations had a significantly earlier onset of atypical absences than individuals with non-truncating mutations (17 vs 28 months, p < 0.05). A similar trend was seen for the age of onset of the first ever seizure, myoclonic seizures, prolonged febrile seizures and status epilepticus; however these differences did not reach statistical significance. Comparing the overall occurrence of seizure types, no differences could be seen between the truncating and non-truncating group. Conclusions: A specific type of mutation (truncating mutation) is associated with an earlier onset of hemi-clonic seizures and atypical absences in Dravet Syndrome. It appears that missense and truncating mutations in SCN1A related Dravet Syndrome result in similar seizure types but different ages of onset. The nature of the SCN1A mutation influences the temporal evolution of disease but not the overall occurrence of seizures.