Abstracts

Rationale: Mutations in the SCN2A gene have recently been associated with a wide spectrum of early onset epilepsies ranging from benign familial neonatal-infantile seizures (BFNIS) and genetic epilepsy with febrile seizures plus (GEFS+) to more severe phenotypes including Ohtahara syndrome (OS), early-onset epileptic encephalopathies (EOEEs) and Dravet syndrome (DS). Cases of BFNIS tend to be dominantly inherited SCN2A missense mutations, whereas severe phenotypes are mainly associated with a de novo missense or truncation mutations. To date little evidence exists that the genotype of a SCN2A missense mutation is reflected in the phenotype of that individual. Methods: We analysed whether there is an association between the nature of a missense mutation and the epilepsy phenotype in 29 cases with SCN2A missense mutations (11 BFNIS and 18 OS/EOEE/DS). In order to grade the change in protein residue substitution we used the Grantham Score (GS), a formula for difference between amino acids combining properties such as the amino acid composition, polarity and molecular volume. We correlated the GS with the overall epilepsy phenotype. Results: We calculated the physico-chemical difference between amino acid changes among the 11 BFNIS missense mutations showing a median GS of 29 (semi-IQR = 11). Whereas the physico-chemical difference for the 18 SCN2A mutations associated with Ohtahara syndrome, EOEEs and Dravet syndrome revealed a median GS of 62 (semi-IQR = 20). The Grantham score of the group with epileptic encephalopathies was significantly higher compared to the GS of the BFNIS group (p = 0.031; Mann-Whitney U test). Conclusions: Our data show that differences in amino acid properties expressed as Grantham Score correlate with significant differences in clinical presentation suggesting that a greater GS is associated with a more severe phenotype. This may give new insights into the significance of missense mutations in SCN2A related epilepsies and may assist genetic counselling.