Fenfluramine in Rett syndrome: A multidimensional clinical study

OBJECTIVE: Rett syndrome (RTT) is a severe neurodevelopmental disorder frequently associated with drug-resistant epilepsy, autonomic dysfunction, respiratory abnormalities, sleep disturbances, and behavioral impairment. Fenfluramine has shown efficacy in developmental and epileptic encephalopathies and may provide broader therapeutic benefits through modulation of serotonergic and sigma-1 receptor pathways. METHODS: We conducted a prospective, open-label, single-center study to evaluate the efficacy, safety, and tolerability of adjunctive fenfluramine in patients with classic RTT carrying pathogenic MECP2 variants. Clinical assessments were performed at baseline and after 3 and 6 months of treatment. Outcomes included seizure frequency; clinician-reported measures of RTT severity, including the Clinical Global Impression-Improvement (CGI-I) scale, Clinical Severity Scale (CSS), and Motor Behavior Assessment (MBA); caregiver-reported measures, including the Rett Syndrome Behavior Questionnaire (RSBQ), Sleep Disturbance Scale for Children (SDSC), the EQ-5D-5L quality of life scale; and neurophysiological measures using auditory evoked potentials. RESULTS: Eight patients with classic RTT and drug-resistant epilepsy were included. Median age was 12 years (range, 6-17 years), and the median number of previously failed antiseizure medications was 5 (range, 2-10). All patients achieved a >50% reduction in seizure frequency. Significant improvements were observed in clinician-reported outcomes, including CGI-I, CSS, and MBA scores, and in caregiver-reported behavioral symptoms assessed with the RSBQ at 3 and 6 months (-7 and -9, respectively). Sleep disturbances improved markedly, with normalization of SDSC scores in all patients by month 6. Respiratory dysfunction, including hyperventilation-related symptoms, improved during follow-up. Neurophysiological assessments showed improved attentional and auditory discrimination processing in a subset of patients. Adverse events occurred in 71% of patients, most commonly somnolence; no patient discontinued treatment because of tolerability issues. SIGNIFICANCE: Fenfluramine was associated with clinically meaningful improvements across several symptom domains in patients with RTT, including seizures, respiratory dysfunction, behavior, sleep, and overall disease severity, with an acceptable safety profile. Further evaluation of fenfluramine as a potential multisymptomatic treatment strategy in RTT in prospective controlled studies is warranted. PLAIN LANGUAGE SUMMARY: Rett syndrome is a rare genetic disorder with complex symptoms that affect many aspects of daily life. In this study, fenfluramine was associated with improvements in seizures and several other important symptoms, including behavior, sleep, breathing, and clinical severity. The treatment was generally well tolerated. These results support further studies to determine whether fenfluramine could become a treatment for multiple symptoms of Rett syndrome.