It is proposed that FFA's effectiveness stems from its ability to address two core pathologies of SV2A deficiency: correction of the excitatory/inhibitory imbalance by restoring inhibitory tone through its serotonergic mechanism, and mitigation of neuroinflammation, thereby stabilizing the neuronal network.
Abstract
Pathogenic SV2A gene variants have been reported as causes of epilepsy and are often associated with drug resistance and susceptibility to fever-related seizures. No highly effective treatments have been established for this condition. We report a female patient with a family history of epilepsy who developed generalized seizures associated with fever and bathing from 6 months of age. Despite intensive treatment with multiple anti-seizure medications, the seizures remained refractory. Given the severe drug-resistant epilepsy characterized by fever sensitivity, seizure clustering, and multiple seizure types suggestive of Dravet syndrome, fenfluramine (FFA) was initiated at 2 years and 2 months of age. FFA at 0.2 mg/kg/day resulted in immediate and sustained seizure freedom. Subsequent whole-exome sequencing identified a pathogenic SV2A variant (p.Gly660Arg). This is the first report demonstrating the clinical efficacy of FFA for epilepsy associated with an SV2A variant. We propose that FFA's effectiveness stems from its ability to address two core pathologies of SV2A deficiency: correction of the excitatory/inhibitory imbalance by restoring inhibitory tone through its serotonergic mechanism, and mitigation of neuroinflammation, thereby stabilizing the neuronal network. FFA may represent a promising therapeutic option for patients with SV2A variant-associated epilepsy, particularly those with a fever-sensitive, drug-refractory phenotype; however, further studies with larger case series are needed to confirm its efficacy.
A child with SCN1A-related ‘genetic epilepsy with febrile seizures plus’ (GEFS+) presented in infancy with recurrent febrile and afebrile seizures, frequently progressing to generalised tonic-clonic status epilepticus. Despite a severe seizure burden and typical Dravet-like triggers, neurodevelopment remained entirely normal and a familial SCN1A variant supported a diagnosis of GEFS+. The variant (c.5666T>A, p.Met1889Lys) was classified as a variant of uncertain significance fulfilling PM2, PP1 and PP3 criteria and absent from The Genome Aggregation Database (gnomAD) and ClinVar. Identification of the same variant in a neurodevelopmentally normal parent supported inherited GEFS+ rather than Dravet syndrome. After treatment failure with sodium valproate, clobazam and topiramate, low-dose fenfluramine (2.2 mg/day, 0.15 mg/kg/day) achieved seizure freedom maintained for more than 1 year with no adverse effects. This dose is substantially lower than the 0.2–0.7 mg/kg/day used in Dravet syndrome trials, suggesting GEFS+ may require lower therapeutic thresholds.
Five novel HCN1 variants are reported here and trends in ASM efficacy are similar to what has been observed in Dravet syndrome, another EIEE, raising questions about potential common pathogenic mechanisms at a cellular level.
Marium N Khan, N. Poolos· Epilepsia Open· 0 citations
In two patients with SCN2A epileptic encephalopathy, treatment with personalized allele-selective antisense oligonucleotides led to a decrease in seizure frequency with a positive safety profile, and a pathway from n = 1 to n of more patients with SCN2A-RD and other monogenic disorders is provided.
Olivia Kim-Mcmanus, L. Mignon, J. Douville et al.· Nature Medicine· 2 citations
This case expands the clinical spectrum associated with RFX3 variants, supporting a potential role in IESS and early neurodevelopmental disruption, and highlights the relevance of including RFX3 in the genetic evaluation of patients with IESS and co-occurring neurodevelopmental disorders.
Graziana Ceraolo, Giulia Spoto, M. Trivisano et al.· International Journal of Mol...· 0 citations
Ettiologic heterogeneity and phenotype overlapping between PDE and PRE, atypical presentations, and good initial response to pyridoxine regardless of genetic and neuroimaging findings suggest the introduction of pyridoxine in all infants when two ASMs have failed.
Ružica Kravljanac, Biljana Vucetic Tadic, Vladimir Oparnica· Frontiers in Neurology· 0 citations
Objective Valproic acid (VPA) response in pediatric epilepsy shows high variability. This study investigated the association of tryptophan hydroxylase-2 (TPH2) polymorphisms with VPA efficacy and adverse drug reactions (ADRs) in children. Methods In a retrospective cohort of 199 children with epilepsy receiving VPA treatment, TPH2 rs4570625 and rs1386494 were genotyped using Sequenom MassArray. Efficacy was categorized as uncontrolled seizure vs. seizure-free. ADRs were systemically recorded, and steady-state VPA concentrations were measured. Network pharmacology integrated protein-protein interactions, and functional enrichment to elucidate TPH2’s role in VPA-related neurotoxicity. Results The rs4570625 polymorphism was significantly associated with VPA treatment outcomes. GG homozygotes exhibited higher seizure-free rates (p = 0.031) and lower incidence of neurological ADRs (p = 0.036). GG carriers also displayed significantly higher VPA serum concentrations. Network pharmacology analyses identified the serotonergic synapse as the dominant enriched pathway linking TPH2 to VPA neurotoxicity, with MAOA and SLC6A4 as key regulatory hubs. No significant associations were observed between rs1386494 polymorphism and VPA treatment outcomes. Conclusion TPH2 rs4570625 may serve as a potential exploratory biomarker for predicting VPA efficacy and neurological toxicity in pediatric epilepsy, mediated through serotonergic pathway dysregulation. Genotype-guided personalization could optimize VPA therapy.
Jiahao Zhu, Xixuan Wang, Xianhuan Shen et al.· Frontiers in Pharmacology· 0 citations
