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Use of fenfluramine in MECP2-related Rett syndrome: Findings from a retrospective multicenter pediatric case series
Silvia Boeri1, Erica Cognolato2, Davide Simonetta1
1Child Neuropsychiatry Unit, IRCCS Giannina Gaslini Children Hospital - Genoa, Italy - Full Member of European Research Network ERN Epicare, Italy; Department of Neurosciences, Rehabilitation, Ophthalmology, Genetics and Maternal and Child Health, University of Genoa, Genoa, Italy; University of Genova, Genoa, Italy.
Insights
Fenfluramine (FFA) shows promise in treating drug-resistant epilepsy in Rett syndrome (RTT) patients, significantly reducing seizure frequency and improving behavior. Further research is needed to confirm these findings in larger populations.
Area of Science:
- Neuroscience
- Pharmacology
- Genetics
Background:
- Rett syndrome (RTT) is a severe neurodevelopmental disorder in females, often accompanied by drug-resistant epilepsy.
- Existing antiseizure medications (ASMs) have limitations, and novel treatments are needed.
Purpose of the Study:
- To evaluate the efficacy and safety of fenfluramine (FFA) in pediatric patients with MECP2-related RTT and drug-resistant epilepsy.
- To assess FFA's impact on seizure frequency, behavioral changes, and adverse events.
Main Methods:
- Retrospective chart review of four pediatric RTT patients treated with FFA.
- Data collection included seizure outcomes, behavioral changes, and adverse effects from 2019-2025.
Main Results:
- Three of four patients showed significant seizure reduction (>50% in two cases), particularly for tonic-clonic seizures.
- Two patients experienced reported improvements in alertness, interaction, and reduced irritability.
- One patient discontinued FFA due to lack of efficacy; mild adverse events resolved upon temporary discontinuation.
Conclusions:
- Fenfluramine (FFA) appears effective and generally well-tolerated for drug-resistant epilepsy in RTT.
- Observed cognitive and behavioral improvements may link to FFA's mechanism and reduced seizure burden.
- Larger prospective studies are warranted to validate FFA's efficacy, safety, and long-term outcomes in RTT.
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.
