Long-term response of fenfluramine in Pediatric CDKL5 deficiency disorder with Lennox–Gastaut syndrome: A case report

Introduction CDKL5 deficiency disorder (CDD) is a severe developmental and epileptic encephalopathy characterized by early-onset, highly drug-resistant epilepsy and profound neurodevelopmental impairment. Seizures often evolve from early focal or tonic seizures through infantile epileptic spasm syndrome and may later transition into a Lennox–Gastaut syndrome (LGS) phenotype. Effective treatment options remain limited. Fenfluramine (FFA), a serotonergic agent approved for Dravet syndrome and LGS, has recently emerged as a potential therapy for CDD, but clinical evidence is scarce. Case presentation We report a 13-year-old girl with CDD who developed seizures at 3 months of age. Over time she experienced multiple seizure types, including generalized tonic–clonic seizures and epileptic spasms, and her epilepsy evolved into an LGS phenotype. Genetic testing identified a de novo heterozygous CDKL5 variant (c.530A>G, p.Y177C). Despite treatment with eight antiseizure medications, adrenocorticotropic hormone therapy, and a ketogenic diet, seizures remained highly refractory. At 13 years, electroencephalography showed generalized slow spike-and-wave discharges consistent with LGS. Low-dose FFA (0.2 mg/kg/day) was initiated, resulting in complete cessation of daily GTCS and clusters of epileptic spasms within a few days. Seizure freedom has been maintained for more than 11 months without clinically significant adverse effects. Conclusion This case illustrates a sustained seizure response to low-dose FFA in a patient with CDD and LGS. However, as a single observation it cannot establish efficacy, and the favorable outcome may reflect responsiveness of the LGS phenotype. FFA should therefore be considered a potential option for refractory CDD, and further studies are needed.