These prediction models demonstrate the feasibility of early prognostication in KCNQ2-RD and support future prospective external validation and enable more accurate individualised counselling by integrating clinical and genetic information readily available at time of genetic diagnosis.
CASK-related disorders may present with severe neurodevelopmental impairment and cerebral palsy–like phenotypes, even in the absence of characteristic neuroimaging findings, which should raise suspicion for CASK-related disorders.
I. Pacheva, Elena Timova, T. Todorov et al.· Frontiers in Psychiatry· 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
Background and Objectives KCNT1-related epilepsy is an ultra-rare pediatric-onset developmental and epileptic encephalopathy with a broad clinical phenotype ranging from, most commonly, severe infantile-onset epilepsy and global developmental delay to, less commonly, milder phenotypes including sleep-related seizures, autism spectrum disorder, and learning disability. We initiated the first-ever prospective natural history study to comprehensively clinically phenotype individuals affected by this disorder. Methods The primary aim of this study was to characterize seizures in individuals with KCNT1-related epilepsy. Secondary and exploratory aims included characterization of the full spectrum of disease symptoms, understanding caregiver burden, and collection of blood and urine samples for biomarker exploration. All study activities were conducted remotely (e.g., home-based assessments, telehealth visits). Results Thirty-five participants (n = 20 male, 15 female) were enrolled in this study. The average age at the baseline visit was 76.0 months (s.d. = 75.5). This article presents the study design and methods and several challenges that arose in its implementation and discusses various solutions implemented in this medically complex population. Discussion Future work will apply the lessons from this study in the planning and design of clinical trials for KCNT1-related epilepsy and possibly other developmental and epileptic encephalopathies.
Heather R. Adams, Viet Nguyen, L. Seltzer et al.· Neurology: Genetics· 0 citations
To summarize the clinical and genetic characteristics of
DNM1L
-related disorders and explore genotype-phenotype correlations and prognosis.
We retrospectively analyzed clinical data from 18 children with
DNM1L
variants diagnosed between 2015 and October 2025. Combined with systematic literature review (2007-October 2025) to analyze reported
DNM1L
variant types and clinical phenotypes.
The cohort included 18 children (10 male, 8 female) with a median onset age of 3.5 years. Epilepsy occurred in 88.9% of patients, with 72.2% developing super-refractory status epilepticus; 66.7% had dystonia. Most patients exhibited brain MRI and EEG abnormalities. Eight novel pathogenic variants were identified (four missense, three frameshift, one compound heterozygous). Notably, eight patients with middle domain variants (primarily p.Arg403Cys) presented a novel “hemiconvulsion-hemiplegia-epilepsy syndrome” phenotype. At last follow-up, 83.3% had a modified Rankin Scale score ≥4, indicating severe disability and poor prognosis. Literatures review confirmed
DNM1L
variants are predominantly missense, with the middle domain as a hotspot. The p.Arg403Cys variant is recurrent and highly prevalent in the Chinese. Middle domain variants are more common in Asians, while GTPase domain variants are more frequent in Europeans. Missense variants in the middle domain correlated with higher rates of neurological dysfunction and mortality.
This study represents an extension of our earlier work by incorporating an additional 18 cases, which expands the genetic and phenotypic spectrum of
DNM1L
-related disorders. It identifies “hemiconvulsion-hemiplegia-epilepsy syndrome” as a distinct feature and potential prognostic indicator for middle domain variants. The established genotype-phenotype patterns, based on protein domains and ethnic differences, provide critical insights for precise diagnosis and management.
Han Xu, Chaolong Xu, Ying Zou et al.· Frontiers in Neurology· 0 citations
PPP1R21-related neurodevelopmental disorder (PPP1R21-NDD) is an ultra-rare autosomal-recessive encephalopathy caused by dysfunction of the Five-subunit Endosomal Rab5 and RNA/ribosome intermediarY (FERRY) complex. To delineate the clinical, neuroimaging, and molecular spectrum of PPP1R21-NDD and outline diagnostic and research priorities. Targeted searches of PubMed, EMBASE, Scopus, Web of Science, and Google Scholar through January 2026 were performed. Eligible reports included molecularly confirmed biallelic PPP1R21 cases and related functional studies. Two researchers independently extracted individual-level data following narrative review quality criteria. Twenty-five individuals from 21 families harbored 17 distinct variants (15 loss-of-function, 2 missense), all homozygous, reflecting high consanguinity. Profound global developmental delay/intellectual disability was universal; hypotonia near-universal (22/25, 88%). Ambulation was delayed and ataxic when achieved; expressive language was minimal or absent. A recognizable coarse facial gestalt was observed with thick eyebrows, broad nasal bridge, thick lips, and low-set ears. Systemic features included feeding dysfunction and respiratory morbidity requiring gastrostomy or tracheostomy in severe cases. Mortality was 17% (4/24). Neuroimaging showed callosal thinning, white-matter volume loss, ventricular enlargement, and vermian hypoplasia. Patient fibroblasts showed delayed transferrin clearance and elevated proteasome activity, suggesting endosomal dysfunction and proteasome hyperactivation. PPP1R21-NDD is a severe recessive encephalopathy with a convergent phenotype and evidence of endo-lysosomal dysfunction. Diagnosis should be pursued with exome or genome sequencing in patients with characteristic clinical and neuroimaging features, particularly in consanguineous families. Research priorities include natural history studies, standardized magnetic resonance imaging (MRI) protocols, neural disease models, and therapeutic strategies targeting endosomal trafficking.
F. Comisi, G. Di Pasquale, A. Comisi et al.· Neurogenetics· 0 citations
OBJECTIVE
The mechanistic effects of genetic variants underlying genetic neurodevelopmental disorders (NDDs) are widely studied, but the contribution of external factors remains largely unexplored.
METHODS
In this cross-sectional study using the Simons Searchlight population dataset, we examined caregiver-reported environmental exposures and functional outcomes from 970 individuals with (67%) and without (33%) epilepsy across 93 NDDs. The primary outcome was adaptive function (Vineland-3) at last follow-up, with quality of life (Quality of Life Inventory-Disability) and autism symptoms (Social Communication Questionnaire-Lifetime) as secondary analyses.
RESULTS
Compared to individuals with NDDs without epilepsy, individuals with epilepsy had lower adaptive function (p < .001). On multivariable regression analysis, we found positive associations between socioeconomic factors and quality of life (parents' highest educational status: β = .014, p = .013; annual household income: β = .007, p = .021) and negative associations between treatment-related factors and adaptive function (treatment with sodium channel blockers: β = -.087, p = 2.44 × 10-5; hospitalizations: β = -.055, p = 3.65 × 10-7). These associations were mediated by epilepsy duration, etiology, and polytherapy. Results were consistent across sensitivity analyses but were not observed in individuals without epilepsy, suggesting epilepsy-specific effects. Together, environmental exposures explained more variance in developmental outcomes than genetic etiology alone (additional R2 = 19.6%, p = .003). Importantly, the additional variance explained by environmental exposures was different across genes, ranging from ~15% (SCN2A, SLC6A1) to >30% (16p11.2 deletion), suggesting gene-specific vulnerability. Overall, ~60% of variance in developmental outcomes remained unexplained, motivating further studies on genome and exposome influences.
SIGNIFICANCE
Our findings highlight genetic NDDs as genome-informed yet exposure-sensitive disorders. We found several external factors that both represent markers of epilepsy severity and may support early, genetically informed seizure management and careful stewardship of treatment exposures. Prospective, controlled studies are needed to disentangle the developmental effects of the underlying disease from treatment-related factors.
C. Boßelmann, Natasha N. Ludwig, C. Holingue et al.· Epilepsia· 0 citations