Use of fenfluramine in MECP2-related Rett syndrome: Findings from a retrospective multicenter pediatric case series.

INTRODUCTION

Rett syndrome (RTT) is a severe neurodevelopmental disorder mainly affecting females. The patients could experience many comorbidities, including gastrointestinal, breathing, cardiovascular disorders, and seizures, which are often drug-resistant. Many antiseizure medications (ASMs) can be utilized as monotherapy or in combination. Fenfluramine (FFA), has a unique mechanism of action that targets the serotonergic system and sigma-1 receptors, has shown benefit in other epileptic encephalopathies, but data on RTT are lacking.

METHODS

We retrospectively reviewed the charts of four pediatric patients (mean age 11 years, ± 2.6, min, 9 years old, max 14 years old) with MECP2-related RTT and drug-resistant epilepsy, treated with FFA between 2019 and 2025 (mean treatment duration: 10.5 months ± 2.4, min. 9 months, max 13 months - treatment duration was calculated from treatment initiation until study completion, which was uniformly defined as March 2025 (time of first manuscript draft) or until drug discontinuation. Clinical data, seizure outcomes, behavioral changes, and adverse effects were collected through medical records and caregiver interviews.

RESULTS

Three out of four patients experienced a significant reduction in seizure frequency, with > 50% reduction in two cases. Tonic-clonic seizures decreased in all responders. One patient did not show improvement and discontinued FFA. Adverse events (apathy and psychomotor slowing) were reported in one case but resolved after temporary discontinuation. EEGs in responders demonstrated partial improvement with a reduction in interictal abnormalities. No cardiac adverse events were observed. Improvement in alertness and interaction, and reduced irritability were reported in two patients.

DISCUSSION: FFA appears effective and generally well-tolerated in patients with RTT and drug-resistant epilepsy, particularly for generalized tonic-clonic seizures. Cognitive and behavioral improvements reported by caregivers may be attributable to a combination of serotonergic receptor modulation and reduced seizure burden. Despite polytherapy, side effects were minimal. These findings align with existing literature on FFA use in other developmental epileptic encephalopathies. Prospective studies on larger cohorts with long-term monitoring are needed to validate efficacy, safety, and cognitive-behavioral outcomes.