From synaptic dysfunction to targeted intervention: a comprehensive review of STXBP1 encephalopathy and precision therapeutic strategies.

Cross-species analysis of GNB1 I80T encephalopathy: conserved developmental, epileptic and neuronal transcriptome signatures

Clinic-to-Mechanism: Unraveling in-depth molecular dysfunctions caused by a GluN2B C-Terminal deletion in developmental and epileptic encephalopathies.

Developmental and epileptic encephalopathies (DEEs) are severe neurodevelopmental disorders associated with genetic mutations, including some in GRIN genes encoding NMDA receptor (NMDA-R) subunits. Despite affecting the same receptor, each mutation may lead to distinct neurological disorders, emphasizing the necessity of understanding receptor dysfunction to tailor treatments effectively. In a genetic screen of DEEs patients, we identified a de novo pathogenic GRIN2B nonsense mutation, p.Glu839Ter (called GluN2B-E839*), which truncates the C-terminal domain (CTD) of the GluN2B subunit, a poorly characterized region critical for receptor function. This variant was prioritized for functional study due to the limited knowledge about the CTD's role. We fully characterized the clinical presentation of the patient, who displayed intellectual disability, epilepsy, and hyperkinetic behavioral disorders. Molecular and cellular analyses in heterologous systems and patient-derived neurons revealed that GluN2B-E839* subunit assembles correctly with other subunits to form NMDA-Rs but exhibits reduced surface expression, impaired interactions with PSD95, and altered biophysical properties, including reduced current amplitudes, increased magnesium sensitivity, and diminished calcium influx. These dysfunctions likely contribute to impaired synaptic plasticity and DEEs pathophysiology. Our findings highlight the critical role of the GluN2B CTD in NMDA-R function and neuronal signaling and underscore the need for systematic characterization of GRIN variants to improve diagnostic precision and therapeutic targeting for DEEs. This study establishes a robust framework combining complementary experimental approaches with patient-derived preclinical models to link molecular dysfunctions to clinical phenotypes.

PPP1R21-Related neurodevelopmental disorder: Phenotypic delineation, variant spectrum, and pathophysiological mechanisms

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.

Role of STX1A in Parkinson’s disease: evidence, mechanistic hypotheses, and translational perspectives

Parkinson’s disease (PD) is a progressive neurodegenerative disorder characterized by degeneration of substantia nigra dopaminergic neurons, α-synuclein pathology, and widespread synaptic dysfunction. Syntaxin-1A (STX1A), a presynaptic Qa-SNARE protein, is essential for synaptic vesicle fusion and also interacts with proteins involved in ion-channel regulation and neuronal excitability. Several animal, extracellular-vesicle, and peripheral-blood studies have reported reduced STX1A abundance in PD. However, the available evidence is predominantly cross-sectional and does not establish whether STX1A downregulation is a cause of PD pathology, a consequence of neuronal and synaptic loss, or a peripheral correlate of disease. This narrative review critically evaluates evidence linking STX1A to PD and distinguishes experimentally supported observations from mechanistic hypotheses. Potential relationships with calcium dysregulation, mitochondrial injury, ferroptosis, and neuroimmune signaling are discussed as testable models rather than established pathways. Direct evidence connecting STX1A to the gut–brain axis in PD is currently lacking and is therefore considered primarily as a future research direction. The biomarker and therapeutic potential of STX1A remains preliminary because diagnostic performance, disease specificity, longitudinal stability, and causal relevance have not been adequately validated. Future studies using cell-type-specific STX1A manipulation, rescue experiments, electrophysiology, and multicenter longitudinal cohorts are required to define the biological and clinical significance of STX1A in PD.

Epilepsy as a Multiscale Network Disorder: Integrating Precision Therapeutics and Emerging Experimental Platforms

Epilepsy is increasingly recognized as a multiscale network disorder rather than solely a condition of neuronal hyperexcitability, and the coordinated use of complementary human-relevant platforms may help incorporate multiscale mechanistic insights into therapeutic development and evaluation, narrow persistent translational gaps, and support more predictive and mechanism-informed treatment strategies.

A prospective natural history study protocol for clinical trial readiness in synaptic disorders.

OBJECTIVE STXBP1-related disorder (STXBP1-RD) and SYNGAP1-related disorder (SYNGAP1-RD) are two common genetic synaptopathies that are associated with epilepsy, developmental delay, intellectual developmental disorder, and behavioral problems. Both STXBP1-RD and SYNGAP1-RD are potential targets for disease-modifying therapies, but there is limited information in the literature describing the natural history of either disorder, which impedes outcome selection for future clinical trials. The objective of this study is to develop a framework to better define and outline the clinical spectrum and longitudinal trajectories of STXBP1-RD and SYNGAP1-RD natural history, including development, behavior, seizure histories, and electrophysiology. METHODS Here, we describe a protocol, regulatory structure, and supportive preliminary data for multicenter, prospective natural history studies of STXBP1-RD (STARR) and SYNGAP1-RD (ProMMiS). The protocols incorporate gold standard clinician-administered outcome measures including the Bayley Scales of Infant and Toddler Development 4th edition, Gross Motor Function Measure-66, fine motor domains of the Peabody Developmental Motor Scales 3rd edition, parent-reported outcome measures, epilepsy histories, and biomarker exploration. To date, the study has enrolled 164 individuals with STXBP1-RD and 159 with SYNGAP1-RD, with ongoing longitudinal assessments every 6 months in a subset of approximately 200 total individuals across both disorders. RESULTS Our data support that existing developmental measures are feasible, informative, and show minimal floor or ceiling effects. Furthermore, we demonstrate that medical record-based seizure history reconstruction reveals unique epilepsy trajectories while minimizing burden to families. We observe disease-specific patterns of developmental performance and distinct longitudinal seizure dynamics, highlighting the need for data generation in a gene/disorder-specific manner for clinical trial readiness. SIGNIFICANCE In summary, we present a feasible natural history protocol with prospective data for two complex neurodevelopmental disorders with natural histories that have previously been incompletely characterized, within a regulatory framework that will support the use of these data to expedite clinical trial development.