Fenfluramine in refractory SCN1A-related 'genetic epilepsy with febrile seizures plus'

Area of Science:

• Genetics
• Neurology
• Pharmacology

Background:

• SCN1A-related epilepsy encompasses a spectrum of disorders, including Genetic Epilepsy with Febrile Seizures Plus (GEFS+) and Dravet Syndrome.
• Distinguishing between GEFS+ and Dravet Syndrome can be challenging, particularly with overlapping clinical presentations and genetic variants.
• Normal neurodevelopment in the presence of significant seizure burden is atypical for severe SCN1A channelopathies.

Purpose of the Study:

• To report a case of SCN1A-related GEFS+ with normal neurodevelopment.
• To investigate the efficacy of low-dose fenfluramine in a GEFS+ patient refractory to other anti-epileptic drugs.
• To explore potential differences in therapeutic thresholds between GEFS+ and Dravet Syndrome.

Main Methods:

• Clinical case presentation and genetic variant analysis (c.5666T>A, p.Met1889Lys) in an infant with epilepsy and a neurodevelopmentally normal parent.
• Classification of the SCN1A variant using ACMG/AMP criteria.
• Pharmacological intervention with low-dose fenfluramine after failure of conventional treatments.

Main Results:

• The patient, diagnosed with GEFS+ based on familial SCN1A variant and normal neurodevelopment, experienced persistent seizures despite multiple anti-epileptic drugs.
• Low-dose fenfluramine (0.15 mg/kg/day) resulted in complete seizure freedom for over one year without adverse effects.
• The effective fenfluramine dose was significantly lower than typically used in Dravet Syndrome trials.

Conclusions:

• SCN1A-related GEFS+ can present with normal neurodevelopment despite severe seizures.
• Low-dose fenfluramine is a promising and effective treatment for refractory GEFS+.
• GEFS+ may necessitate lower therapeutic fenfluramine dosing compared to Dravet Syndrome, indicating distinct pharmacological profiles.