Clinical and genetic factors predicting Dravet syndrome in infants with SCN1A mutations

Abstract

Objective: To explore the prognostic value of initial clinical and mutational findings in infants with SCN1A mutations.

Methods: Combining sex, age/fever at first seizure, family history of epilepsy, EEG, and mutation type, we analyzed the accuracy of significant associations in predicting Dravet syndrome vs milder outcomes in 182 mutation carriers ascertained after seizure onset. To assess the diagnostic accuracy of all parameters, we calculated sensitivity, specificity, receiver operating characteristic (ROC) curves, diagnostic odds ratios, and positive and negative predictive values and the accuracy of combined information. We also included in the study demographic and mutational data of the healthy relatives of mutation carrier patients.

Results: Ninety-seven individuals (48.5%) had Dravet syndrome, 49 (23.8%) had generalized/genetic epilepsy with febrile seizures plus, 30 (14.8%) had febrile seizures, 6 (3.5%) had focal epilepsy, and 18 (8.9%) were healthy relatives. The association study indicated that age at first seizure and frameshift mutations were associated with Dravet syndrome. The risk of Dravet syndrome was 85% in the 0- to 6-month group, 51% in the 6- to 12-month range, and 0% after the 12th month. ROC analysis identified onset within the sixth month as the diagnostic cutoff for progression to Dravet syndrome (sensitivity = 83.3%, specificity = 76.6%).

Conclusions: In individuals with SCN1A mutations, age at seizure onset appears to predict outcome better than mutation type. Because outcome is not predetermined by genetic factors only, early recognition and treatment that mitigates prolonged/repeated seizures in the first year of life might also limit the progression to epileptic encephalopathy.

Figure 1. Schematic representation of SCN1A mutations identified in this study

Nomenclature of mutations followed recommendations of the Human Genome Variation Society.

Figure 2. Pedigrees of families exhibiting incomplete penetrance of SCN1A mutations

= Dravet syndrome; = FS; = generalized/genetic epilepsy with febrile seizures plus; = focal epilepsy; +/− = heterozygous SCN1A mutation; +/+ = absence of the SCN1A mutation.