Rationale:
There is a growing body of evidence showing that pathogenic mutations in genes regulating sodium channels are pertinent in the selection of appropriate anti-seizure medication for children with epilepsy. Sodium channel blockers are known to aggravate seizures in patients with pathogenic mutations of the SCN1A gene (Pharmacol Rev 2018; 70; 147–149). Sodium channel blockers are often beneficial for patients with pathogenic mutations of the SCN8A gene (Pharmacol Rev 2018; 70; 151–152). This study was designed to determine whether clinicians alter their choice of anti-seizure medication when presented with a patient’s genetic test results showing a sodium channel mutation. We hypothesized that patients for whom genetic testing results reveal genetic variants that inform a definitive treatment (i.e. pathogenic or potentially pathogenic variants of SCN1A or SCN8A mutations) are likely to change therapy based on these results.
Method:
Chart review was completed on 43 patients with SCN1A gene variants and 6 patients with SCN8A gene variants found on epilepsy gene test panels using next generation sequencing techniques. Variants were classified as: variant of unknown significance (VUS), likely pathogenic, or known pathogenic variant. Benign variants were excluded. Physician notes were reviewed for acknowledgement of gene panel results, changes in antiepileptic medications at the time of the result, and subsequent use of sodium channel blockers.
Results:
Epilepsy gene panel results were acknowledged in the patient’s chart in a timely manner for 86% of patients with SCN1A variants and 100% of patients with SCN8A variants. Anti-seizure medications were changed in 30% of all patients whose gene panel results were acknowledged, and in 66% of patients with a known pathogenic mutation.
For patients with SCN1A variants whose gene panel results were acknowledged, anti-seizure medications were changed in 3 of 21 patients with VUS, 1 of 6 patients with likely pathogenic variants, and 6 of 10 patients with pathogenic mutations.
For patients with SCN8A variants, anti-seizure medications were changed in 1 of 4 patients with VUS, and both of the 2 patients with likely pathogenic variants.
Of the 31 patients with SCN1A mutations whose gene panel results were acknowledged, 8 of these patients were later prescribed sodium channel blockers. Of these, 6 patients had VUS, and 2 had likely pathogenic variants.
Of the 6 patients with SCN8A variants, 5 were later prescribed sodium channel blockers. Of these, 3 patients had VUS and 2 had likely pathogenic variants.
Conclusion:
We conclude that the results of genomic tests for epilepsy genes SCN1A and SCN8A inform selection of anti-seizure medication, with 83% of patients with SCN8A variants treated with sodium channel blockers compared to only 25% of patients with SCN1A variants and none of the patients with pathogenic SCN1A mutations. Furthermore, physicians are more likely to make changes to a patient’s current antiepileptic drugs in patients with pathogenic or likely pathogenic variants than in patients with VUS.
Funding:
:none
FIGURES
Figure 1