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.
Abstract
SCN2A variants are among the most common genetic causes of developmental and epileptic encephalopathies (DEEs), which can present with uncontrolled seizures at birth and account for 1–2% of all epileptic encephalopathies. A substantial fraction of causal variants are gain-of-function or mixed-function variants associated with increased channel open probability or greater sodium current flux. Here two parallel n = 1 clinical studies were conducted in two patients (9-year-old and 14-year-old boys) with SCN2A-related DEE. Individualized allele-selective antisense oligonucleotides (ASOs) were designed to target heterozygous intronic single-nucleotide polymorphisms (SNPs) for decreased expression of mutant SCN2A transcript while preserving the wild-type copy. Primary endpoints included quantitative change from baseline in seizure frequency and neurodevelopment, including motor scores. Efficacy measures were also individualized to each patient’s phenotype, including refractory seizures, developmental delay, autism spectrum disorder, choreoathetosis and gastrointestinal dysfunction. Patients experienced a reduction in seizure frequency (26% and 90% in the two patients, respectively), decreased use of concomitant medications and improvement in neurodevelopmental skills. Both ASOs were well tolerated, with no ASO-related serious adverse events. Continued long-term follow-up of these preliminary positive safety and efficacy findings is needed to confirm the disease-modifying potential of these ASOs. Haplotype phasing in a separate cohort of infants with SCN2A-related disorder (SCN2A-RD), diagnosed by rapid whole-genome sequencing, identified 16% of patients with compatible SNPs. These data provide a pathway from n = 1 to n of more patients with SCN2A-RD and other monogenic disorders. ClinicalTrials.gov registration: NCT06314490. 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.
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
The gene most commonly implicated in epilepsy, SCN1A, encodes the neuronal voltage-gated sodium channel subunit NaV1.1. SCN1A variants that reduce sodium current (“loss of function” variants) cause Dravet syndrome, a neurodevelopmental disorder defined by treatment-resistant temperature-sensitive epilepsy with onset at/around 5 months of age, developmental delay/intellectual disability, and features of or formal diagnosis autism. However, an emerging group of variants cause “gain of function” (GoF) effects on NaV1.1 and result in a distinct presentation with earlier onset than Dravet syndrome and prominent movement disorder but without temperature sensitivity. We developed the first mouse model of SCN1A GoF epilepsy with heterozygous Cre-dependent expression of the recurrent patient variant Scn1a-p.R1636Q. Global expression of this variant causes premature mortality in 100% (64/64) of mutant mice between postnatal day 12-18 due to spontaneous, convulsive seizures. Activation of the mutant allele in parvalbumin interneurons (Dlx5/6-Cre or PV-Cre), but not excitatory neurons (Slc17a7-Cre) or other interneuron subtypes (VIP-Cre or Sst-Cre), recapitulates the premature mortality and epilepsy phenotypes. Treatment of Scn1a-p.R1636Q mutant mice with the sodium channel blocker GS967 markedly prolongs lifespan. This work is the first study of SCN1A GoF epilepsy in a preclinical model in vivo. Further investigation in the Scn1aflox(R1636Q)mouse will yield new mechanistic insights into disease mechanisms to drive advances in the treatment of SCN1A GoF epilepsy.
Sophie F. Hill, Z. P. Rosenthal, Ethan M. Goldberg· bioRxiv· 0 citations
Pathogenic KCNQ2 variants are the most common genetic cause of neonatal-onset epilepsies, with phenotypes ranging from self-limited (familial) neonatal epilepsy (SeL(F)NE) to severe developmental and epileptic encephalopathy (KCNQ2-DEE). Sodium channel blockers (SCBs) have shown promise for seizure control in these disorders, but their impact on neurodevelopmental outcomes and possible relationship with timing of initiation remain incompletely understood. We leveraged a large, multicentre international cohort comprising 282 individuals with pathogenic KCNQ2 variants to retrospectively assess the effectiveness of antiseizure medications (ASMs), particularly SCBs, on seizure control and neurodevelopment. Individuals were grouped according to the predicted variant-specific functional effects: loss-of-function (LOF) variants known to be associated with SeL(F)NE or DEE respectively, and gain-of-function (GOF) variants. Epilepsy course, ASM effectiveness, and neurodevelopmental milestones were systematically collected and analysed, including time-to-event and adjusted outcome analyses. SCBs, especially carbamazepine (CBZ) and oxcarbazepine (OXC), emerged as the most effective ASMs in both LOF groups. In LOF KCNQ2-DEE, time-to-event analyses showed that early SCB initiation (≤1 month) was associated with earlier seizure offset. Early SCB initiation was also associated with significantly more favourable neurodevelopmental outcomes, including higher rates of attaining major motor milestones. This association remained significant after adjustment for seizure control by 1 month and total ASM burden. Considerable phenotypic variability persisted, with some individuals experiencing severe impairment despite early seizure control and SCB initiation, suggesting that variant severity and additional genetic or biological modifiers contribute to outcome heterogeneity.Our results support the use of SCBs, particularly CBZ and OXC, as first-line therapy in (LOF) KCNQ2-DEE and SeL(F)NE. Earlier SCB initiation was associated with earlier seizure offset and more favourable developmental outcomes, underscoring the importance of early genetic diagnosis and timely SCB therapy. We however emphasise that early treatment is not universally transformative and further prospective work, including exploration of targeted therapies and standardised neurodevelopmental assessments, is needed to optimise long-term outcomes in this heterogeneous population.
C. Millevert, M. Hairabedian, Samuel Dahan et al.· Brain : a journal of neurolo...· 0 citations
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.
Prime editing of a pathogenic Scn1a allele ameliorates seizure phenotypes in a GEFS(+) mouse model Kissling L, Pietrafesa F, Ranucci M, Bock D, Mathis N, Kulcsar PI, Ioannidi E, Schmidheini L, Talas A, Villiger E, Wildner H, Zhao X, Kompotis K, Zeilhofer HU, Schwank G. Sci Transl Med. 2026;18(849):eadz2557. Generalized epilepsy with febrile seizures plus (GEFS+) is an inherited epileptic disorder predominantly linked to autosomal-dominant, loss-of-function mutations in the sodium voltage-gated channel α subunit 1 (SCN1A) gene, which encodes the α subunit of the neuronal voltage-gated sodium ion channel type 1 (NaV1.1). Reduced NaV1.1 function in γ-aminobutyric acid (GABA)-ergic interneurons impairs inhibitory signaling and leads to neuronal hyperexcitability. Clinically, GEFS+ is characterized by a spectrum of seizure types, often beginning with febrile seizures in early childhood and progressing to generalized tonic-clonic seizures later in life. Here, we used prime editing to correct the pathogenic SCN1A-K1270 T mutation in the Scn1aKT/+ mouse model of GEFS+. Adeno-associated viral (AAV) vectors were used to deliver an intein-split prime editor under the control of a neuron-specific promoter into the cerebral ventricles of neonatal mice. This enabled efficient in vivo editing, achieving 34.7 ± 14.5% correction of the mutant allele in cortical bulk DNA, 81.2 ± 5.9% correction of mRNA, and improved multiple disease-relevant phenotypes. Survival increased from 80% in control-treated animals to 100% in treated mice, cortical inhibitory neuron transmission was improved (frequencies of inhibitory postsynaptic currents were increased from 0.32 to 1.32 hertz), and the frequency of induced febrile seizures decreased from 78.6% to 13.3%, approaching the frequency seen in wild-type mice (8%). These findings suggest the therapeutic potential of prime editing for the treatment of patients with SCN1A-associated GEFS+. In vivo adenine base editing ameliorates Dravet syndrome phenotypes in a mouse model Nelson AT, Hill SF, Simon M, Clatot J, Sakai HA, Xie J, Sousa AA, An M, Gao G, Lutz CM, Goldberg EM, Liu DR. Sci Transl Med. 2026;18(849):eadx5999. Dravet syndrome (DS) is a severe neurodevelopmental disorder characterized by drug-resistant epilepsy, temperature-sensitive seizures, cognitive impairment, and a high incidence of sudden unexpected death in epilepsy (SUDEP). DS is caused by loss-of-function variants in SCN1A, which encodes the α subunit of the voltage-gated sodium channel (Nav1.1). Current approved treatments manage symptoms of DS but do not correct the root cause of the disease. Here, we describe the use of an adenine base editor (ABE) to directly correct SCN1AR613X, a recurrent variant found in patients with DS. We identified ABE strategies to efficiently correct R613X in engineered homozygous SCN1AR613X human embryonic kidney 293 T and mouse Neuro-2a cells (72 and 92% correction efficiencies, respectively). We then used a dual-adeno-associated virus serotype 9 (AAV9) approach to deliver an optimized ABE system to Scn1aR613X/+ mice, which recapitulate several key DS pathologies. AAV9-ABE treatment of Scn1aR613X/+ neonates resulted in efficient DNA and mRNA editing (59 and 97%, respectively, in bulk neocortices), restoring parvalbumin-expressing inhibitory neuron excitability and sodium current to wild-type levels. This ameliorated both spontaneous and temperature-induced seizures and led to a 3.3-fold improvement in 45-day survival over vehicle-treated mice (ABE treated, 90%; and vehicle treated, 27%). Last, ABE treatment in 12-day-old mice resulted in a 3.0-fold improvement in 60-day survival over vehicle-treated mice (ABE treated, 82%; and vehicle treated, 27%). In conclusion, these data validate a strategy to correct SCN1A variants with ABE and highlight the potential of precision genome editing treatments for the treatment of DS and possibly other neurodevelopmental disorders.
Samantha A Dow, Tracy A. Bedrosian· Epilepsy Currents· 0 citations
This study may expand the mutation and phenotypic spectrum of SETD1A-related disorders, establishing the relationship between SETD1A variants and isolated early-onset epilepsy without accompanying severe neurodevelopmental deficits, and highlighting the value of genetic testing in infants with unexplained epilepsy.
Rina Su, Lei Zhu, Lin Jiang et al.· Frontiers in Neuroscience· 0 citations