Rikke Steensbjerre Møller

Background and ObjectivesSCN2A disease spans a broad clinical spectrum from self-limited (familial) neonatal-infantile epilepsy to severe developmental and epileptic encephalopathies. Systematic ch...

Objective: Functional (dissociative) seizures (FDS) are increasingly recognized among individuals with epilepsy, intellectual disability (ID), and psychiatric disorders, but their occurrence in PCDH19‐clustering epilepsy (CE) has not been systematically described. We aimed to characterize the clinical features, diagnostic pathways, and management of FDS in individuals with genetically confirmed PCDH19‐CE. Methods: We conducted a multicenter retrospective study across six tertiary European Epilepsy Centers. Individuals with genetically confirmed PCDH19‐CE and a diagnosis of FDS according to the International League Against Epilepsy (ILAE) criteria were included. Demographic, clinical, neuropsychiatric, neurophysiological, neuroimaging, and treatment‐related data were collected from medical records. Results: Among 27 individuals with genetically confirmed PCDH19‐CE, eight (29.6%) experienced FDS. The median age at FDS onset was 16 years. Most affected individuals had some degree of ID, and nearly all exhibited psychiatric comorbidities, particularly behavioral dysregulation and autism spectrum disorder. Six patients were initially misdiagnosed with epileptic seizures, resulting in unnecessary antiseizure medication (ASM) escalation and hospitalizations. Following FDS diagnosis, ASM reduction or modification was undertaken in three patients. Multidisciplinary management involving psychiatry, psychology, and occupational therapy was implemented in most cases, and all treated individuals demonstrated clinical improvement. Significance: FDS may constitute an important comorbidity in individuals with PCDH19‐CE, particularly during adolescence and adulthood. Early recognition of FDS may prevent unnecessary diagnostic and therapeutic interventions, reduce inappropriate ASM escalation, and improve patient outcomes through timely multidisciplinary care.

Objective: Genetic testing plays an increasing role in the diagnostic pathway for rare and complex epilepsies. However, significant heterogeneity persists in access, implementation, and interpretation across Europe. This study aimed to assess genetic testing practices, accessibility, and challenges across expert epilepsy centers within the European Reference Network for Rare and Complex Epilepsies (ERN EpiCARE) and to identify key challenges and areas for harmonization. Methods: A cross‐sectional survey was developed by the ERN EpiCARE Clinical Genetics Working Group and distributed to 50 EpiCARE member centers across 27 European countries. The questionnaire collected quantitative and qualitative information on available genetic testing modalities, turnaround times, use of rapid testing, multidisciplinary team (MDT) organization, genetic counseling practices, and perceived challenges. Survey findings were complemented by a structured discussion held during the ERN EpiCARE General Assembly. Results: Responses were received from 46 centers (51 responses). Most centers reported access to genetic testing, predominantly through in‐house facilities. Whole‐exome sequencing was available in 85% of centers, and gene panels were available in 78%. Whole‐genome sequencing was available in 59% of centers, frequently restricted to research or performed externally. Turnaround times for standard genetic testing were most commonly between 1 and 6 months. Genetic testing strategies varied by epilepsy subtype, with gene panels most frequently used as first‐tier testing, and exome sequencing preferentially applied in developmental and epileptic encephalopathies. Considerable heterogeneity was observed in MDT organization, access to genetic counseling, reimbursement, data‐sharing and registry infrastructures. Significance: Although genetic testing is widely available across ERN EpiCARE centers, substantial disparities persist in its organization, accessibility, and implementation. Addressing these gaps through strengthened multidisciplinary collaboration, harmonized diagnostic strategies, and enhanced European‐level coordination will be essential to ensure equitable access to high‐quality genetic care for individuals with epilepsy. Plain Language Summary: Genetic testing is increasingly integrated in the diagnostic pathway for rare and complex epilepsies and treatment decisions. An ERN EpiCARE survey assessed how genetic testing is implemented across specialist epilepsy centers in Europe and identified persistent organizational, financial, and clinical barriers. Although most centers had access to advanced genomic testing, important differences were identified in access, reimbursement, turnaround times, and multidisciplinary expertise. European collaboration and harmonized practices are needed to support equitable access to high‐quality genetic care for people living with epilepsy.

Purpose. To develop a proband-level five-tier outcome classification for trio genome sequencing (GS) in neurodevelopmental disorders (NDD), and, in a small subgroup, to explore what is associated with a full versus partial phenotype match to a candidate gene’s disease spectrum. Methods. A rule-based five-tier framework integrating ACMG/AMP classification, ClinGen gene-disease validity, phenotype concordance, and orthogonal validation was applied to 40 probands with unresolved NDD (36 after exclusions); two reviewers assigned tiers by consensus. Phenotype matching used clinician-documented Human Phenotype Ontology terms, characterised against documentation-derived metrics. Results. Of 36 probands, 7 (19.4%; 95% CI 8.2–36.0%) received a confirmed diagnosis (Tier 1) and 5 (13.9%) a high-priority, unvalidated candidate (Tier 3); none were Tier 2 (Provisional). The remainder had a low-priority candidate (22, 61.1%) or no candidate (2, 5.6%). Among 12 probands with strong disease-association evidence, a full phenotype match was associated with richer documentation than a partial match, not a higher similarity score (p = 0.005); this preliminary finding warrants replication. All confirmed diagnoses involved variant types detectable by exome sequencing (ES), not genome-specific findings like deep intronic variants. Conclusion. The five-tier framework resolves the diagnostic intermediate collapsed by binary solved/unsolved reporting. Comprehensive, disease-specific phenotyping is the practical lever for framework performance.

Approximately 75% of individuals with neurodevelopmental disorders (NDD) remain without a molecular diagnosis after first-tier genetic testing, and a substantial share of that gap reflects the pace of gene-disease discovery rather than sequencing technology alone (Stefanski et al., 2021). Here we report trio genome sequencing in 36 probands with NDD or epilepsy who remained molecularly unsolved despite prior genetic testing. Likely pathogenic variants were identified in thirteen probands (36%): eight confirmed diagnoses and five high-priority findings pending Sanger validation, including a deep intronic PPP2R5C variant that extends the gene's recognised mutational spectrum. A further 19 candidate genes without an established disease association were prioritised by evidence score, including PRKAR1B, identified independently as a de novo duplication in two unrelated probands but not counted as a diagnosis pending clarification of its disease mechanism. Grouping all 34 findings by functional theme showed genes involved in transcription and chromatin regulation as the largest category. Only 9% of findings were in genome regions inaccessible to exome sequencing, indicating that most diagnostic value reflected thorough, trio-based analysis rather than access to genome-specific sequence. These findings support genome sequencing as a second-tier diagnostic step after negative prior testing, while showing that reassessing gene-disease validity, not sequencing technology, accounted for part of this yield.

Objective: The semisynthetic compound vinpocetine has gained attention as a potential precision medicine for developmental and epileptic encephalopathies caused by loss‐of‐function (LoF) variants in γ‐aminobutyric acid type A (GABA _A ) receptor genes. As a positive allosteric modulator of GABA _A receptors, case reports suggest that vinpocetine can reduce epileptiform activity and seizure frequency, while improving cognitive function in patients with GABA _A receptor‐related epilepsies. Here, we extend these observations with a retrospective observational study evaluating the response to vinpocetine in an additional seven patients. Methods: Patients initiated treatment with vinpocetine between 2018 and 2025 at the Danish Epilepsy Centre or abroad. Clinical data were collected from medical records, seizure diaries, and neuropsychological assessments. The modulatory efficacy of vinpocetine was investigated using electrophysiological studies. Results: Nine patients harboring eight GABA _A receptor LoF variants were given add‐on vinpocetine treatment. Electrophysiological analyses confirmed dose‐dependent positive modulation by vinpocetine across tested variants. Six patients with a median age of 15.5 years (range = 6–29) continued treatment for a median of 24 months (range = 12–90), whereas three discontinued due to adverse effects (AEs) or lack of efficacy. The patients' level of function ranged from normal to moderate intellectual disability, psychiatric comorbidities, and behavioral disturbances. Four patients initiated vinpocetine due to uncontrolled seizures. One became seizure‐free, and two experienced a 50%–55% reduction. Electroencephalograms demonstrated improved spike–wave indexes in four patients. Six showed improvement in nonseizure factors, and caregivers reported reduced aggressivity and better vocabulary in one. Vinpocetine was well tolerated, with only mild and reversible AEs reported. Significance: Adjunctive vinpocetine shows promise as a targeted therapy for patients with GABA _A receptor LoF variants, decreasing seizure frequency and positively impacting nonseizure factors, with only mild AEs reported. Vinpocetine may be a safe and effective therapy for patients with GABA _A receptor‐related epilepsies, which should be investigated further in future N ‐of‐1 trials.

Gain-of-function variants (GOF) in SCN8A , which encodes the Na _V 1.6 sodium channel, lead to epilepsy syndromes ranging from drug-responsive self-limited (SeLIE) and intermediate epilepsy to drug-resistant developmental and epileptic encephalopathy (DEE). It is currently unclear why individuals with SCN8A GOF variants show variable responses to sodium channel blockers (SCBs). Here, we compared the clinical characteristics of 173 individuals with 25 different SCN8A GOF variants following the hypothesis that carriers of variants affecting activation gating respond less well to SCBs than those with variants affecting fast inactivation gating, given that use-dependent SCBs preferentially target inactivated channel states. We found that individuals with variants altering channel activation gating were more severely affected than those with variants altering inactivation properties: They had an earlier age at onset (3 vs. 5 months, P < 0.0001), higher prevalence of DEE (75% vs. 39%; P < 0.0001), and poorer response to SCBs (20% vs. 69% seizure free; P < 0.0001). We performed pharmacological studies on representative and recurrent variants from each group: two variants (F846S and M1760I) causing hyperpolarizing shifts of the voltage-dependent activation curves, and two variants (G1475R and N1877S) causing depolarizing shifts of the voltage-dependent fast inactivation curves. Phenytoin failed to suppress neuronal firing in neurons expressing activation-related variants, but showed good suppressing effects in neurons expressing inactivation-related variants. In contrast, PRAX-330, a new SCB, which showed much faster binding rates than phenytoin, was effective for both groups of variants by markedly reducing neuronal firing through rapidly and persistently stabilizing Na _V 1.6 in the inactivated state. Our findings provide new insights into the mechanism of drug-resistance in SCN8A -DEE and support PRAX-330 and compounds with similar pharmacological properties as a promising preclinical candidate for targeted therapies.

Gain-of-function (GOF) variants in γ-aminobutyric acid type A (GABAA) receptors are increasingly recognized as a cause of severe developmental and epileptic encephalopathies. However, the mechanisms by which enhanced GABAA receptor activity leads to neuronal network hyperexcitability remain unclear. We engineered a new mouse model based on the human GOF GABRB3 p.(Glu77Lys) variant (β3E77K), identified in two individuals diagnosed with developmental and epileptic encephalopathies, to explore the mechanisms underlying GABAA receptor GOF disease. The phenotypes of β3E77K mice included embryonic lethality consistent with a severe early developmental impact of the GOF GABAA receptor variant. These mice display spike-wave-like discharges that were exacerbated by vigabatrin and ameliorated by valproate, matching the clinical observations of GOF GABRB3 patients. β3E77K mice also have increased proconvulsant-induced seizure susceptibility and a broad increase in electrocorticographic spectral power amplitude, indicative of cortical hyperexcitability. Additionally, neurological assessments revealed hypoactivity and weakened grip strength. Ex vivo electrophysiological recordings demonstrated increased GABAA receptor-mediated current amplitudes at both excitatory and inhibitory synapses in CA1 hippocampus, consistent with the GOF molecular phenotype previously identified in functional studies. In cortical layer 2/3, inhibitory interneurons showed increased synaptic GABAA receptor-mediated current amplitude, and synapses onto pyramidal neurons exhibited reduced inhibitory currents. Enhanced GABAA receptor-mediated synaptic activity among layer 2/3 interneuron populations caused a use-dependent collapse of feed-forward inhibition, resulting in increased pyramidal neuron excitability. Computational modelling supported this disinhibition mechanism, showing that enhanced GABAA receptor synaptic strength between interneurons diminishes inhibitory synaptic conductance onto pyramidal cells. Our findings highlight the critical role of interneuron network dysfunction in driving cortical hyperexcitability caused by GOF GABAA receptor variants. They provide a novel pathogenic mechanism in developmental and epileptic encephalopathies that could have broader implications for disorders involving dysfunction in GABAergic neurons. The β3E77K mouse also provides a unique preclinical model to test therapeutic strategies in GOF GABAA receptor disease.

Objective: Neonatal developmental and epileptic encephalopathy with movement disorder and arthrogryposis (NDEEMA) represents the most severe end of the gain‐of‐function (GOF) SCN1A disorder spectrum. Sporadic cases of congenital arthrogryposis have also been reported in individuals with SCN2A‐ , SCN3A‐, and SCN8A ‐related developmental and epileptic encephalopathy. Here, we investigated whether NDEEMA occurs in other brain‐expressed sodium channelopathies and characterized its features. Methods: Individuals with the clinical phenotype of NDEEMA were identified through internal databases, an international network of epileptologists and geneticists, and the literature. Their clinical and genetic information was analyzed. A literature survey was conducted to review studies describing the functional effects of the pathogenic variants. Results: Of 46 NDEEMA individuals, 25 harbored variants in SCN1A , 13 in SCN2A , one in SCN3A, and seven in SCN8A . Thirty‐five different pathogenic/likely pathogenic missense variants were identified, all of which clustered in evolutionary conserved paralogous Na _V positions. Five individuals died in utero. Thirty‐nine of 41 (95%) liveborn individuals developed neonatal epilepsy with tonic seizures and/or apnea. Thirty‐one individuals tried sodium channel blockers, of whom 21 (68%) experienced seizure reduction. All individuals for whom information was available developed movement disorders, with myoclonus, dystonia, and tremor being the most common features. Literature review of functional studies revealed that nine NDEEMA variants, and the corresponding paralogues of 16 additional NDEEMA variants, have been biophysically characterized as GOF. Significance: This study expands the phenotype of NDEEMA from SCN1A to its paralogue sodium channel genes expressed in the brain: SCN2A, SCN3A , and SCN8A .