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Genetic neurodevelopmental disorders (NDDs) encompass a heterogeneous group of conditions characterized by impaired cognitive, behavioral, and neurological development resulting from pathogenic variants affecting brain development and synaptic function. Advances in molecular genetics and next-generation sequencing have significantly expanded the understanding of the genetic architecture underlying disorders such as Rett syndrome (RTT), Fragile X syndrome (FXS), Angelman syndrome (AS), and autism spectrum disorders. Beyond these classical neurodevelopmental disorders, spinal muscular atrophy (SMA) is included as a paradigmatic example of successful RNA-based therapeutic translation. Concurrently, RNA-based therapeutics have emerged as promising precision medicine strategies capable of modulating gene expression at the transcriptional and post-transcriptional levels. These approaches include antisense oligonucleotides (ASOs), small interfering RNAs (siRNAs), messenger RNA (mRNA) therapies, RNA editing technologies, and splice-modulating agents. Recent clinical successes, particularly in spinal muscular atrophy, have demonstrated the transformative potential of RNA therapeutics in neurological disease. However, substantial challenges remain, including BBB penetration, long-term safety, immune activation, and genotype-specific variability in therapeutic response. This review summarizes current advances in RNA-based therapeutics for genetic NDDs, highlighting molecular mechanisms, disease-specific therapeutic strategies, translational progress, delivery challenges, and future directions. Overall, continued progress will depend on the integration of disease biology, rational RNA therapeutic design, and effective CNS-targeted delivery, supporting the broader implementation of precision RNA medicine for genetic neurodevelopmental disorders.

BACKGROUND: Angelman syndrome (AS) is a rare neurodevelopmental disorder with characteristic electroencephalographic abnormalities caused by loss of function of the maternally inherited UBE3A gene. Converging evidence suggests a disrupted excitation-inhibition (E/I) balance toward hyperexcitability. However, noninvasive approaches capable of characterizing intrinsic cortical excitability and its relationship with large-scale brain dynamics in AS are still lacking. We used resting-state electroencephalography (EEG) to derive cortical excitability, testing the hypothesis that altered local E/I balance in AS is associated with instability of large-scale functional brain networks. METHODS: We recorded 7 minutes of task-free high-density EEG in 29 individuals with AS and 36 typically developing control participants. Source-reconstructed cortical activity was used to compute the excitability index (EI), based on mean spatial phase synchronization in the gamma band. Dynamic functional connectivity was computed and summarized as the fluidity index, which estimates temporal variability of network configurations. We assessed group differences and associations between EEG features, clinical variables, and caregiver-reported questionnaires. RESULTS: Participants with AS showed increased EI in the anterior cingulate, dorsolateral prefrontal, temporoparietal, and occipital regions. Fluidity was larger in AS across frequency bands, indicating greater network instability. EI positively predicted fluidity in widespread regions in the AS group, whereas the opposite pattern was observed in the control group. Higher EI correlated with fewer antiseizure medications and greater sensory-seeking behavior. CONCLUSIONS: AS is characterized by cortical hyperexcitability coupled with unstable large-scale network dynamics. EI provides a biologically meaningful marker linking intrinsic E/I imbalance to behavioral features and treatment-related variables.

Childhood-onset movement disorders comprise a heterogeneous group of rare conditions with substantial unmet therapeutic needs. Recent advances in disease gene discovery, mechanistic modeling, and translational platforms have accelerated the development of targeted therapies and enabled innovative clinical trial designs for small patient populations. To review novel and emerging therapies for childhood-onset movement disorders, with a focus on pharmacologic strategies, disease-modifying approaches, and patient-centered precision therapies. We surveyed the literature, major conference proceedings, and expert networks to identify therapies approved, in clinical development, or supported by compelling preclinical data between 2022 and 2025. We focused on small molecules and genetic therapies for conditions in which movement disorders represent a prominent clinical feature. Small molecules were categorized as repurposed or novel drugs, whereas genetic therapies included gene replacement, gene editing, and RNA-based expression modulation. Drug repurposing approaches have shown promise in disorders related to the GNAO1, ATP1A3, ATM, and ADCY5 genes. Novel small molecules have advanced for Friedreich's ataxia and Tourette's syndrome. Gene replacement therapies have demonstrated clinical benefit in select neurotransmitter disorders, whereas gene editing strategies have entered preclinical development for ATP1A3-related disease. Antisense oligonucleotide therapies have yielded encouraging early results across several conditions with prominent movement disorder phenotypes, including KIF1A-related neurological disorder, Angelman syndrome, SCN2A-related neurodevelopmental disorder, and ataxia-telangiectasia. Precision-based therapeutic strategies are rapidly reshaping the treatment landscape for childhood-onset movement disorders. Continued progress will depend on rigorous phenotyping, careful ethical oversight, and deliberate efforts to promote equitable global access to emerging therapies. © 2026 International Parkinson and Movement Disorder Society.

BACKGROUND: Caregivers of children with Angelman syndrome (AS) experience substantial stressors and often experience challenges accessing mental health providers with expertise in their unique family needs. PURPOSE: Community-academic partnerships have potential for ensuring such treatments are deployed in ways that maximally benefit the patient community. METHODS: This study examined the effectiveness of using a community-centered approach to training student clinicians to deploy telehealth acceptance and commitment therapy (ACT) with a pilot sample of caregivers (n = 17) with young children diagnosed with AS. Prior to deploying the treatment, clinicians received community-led training on the unique needs of AS families. RESULTS: Upon completing the abbreviated 9-week protocol, caregivers reported decreases in depression and parenting stress and increases in parenting confidence across treatment, supporting future testing of ACT for AS in the context of randomized control trials. CONCLUSIONS: Our findings support the feasibility of leveraging community-academic partnerships to co-train graduate-level clinicians to deliver ACT to specialized populations. This is also the first study to document preliminary effectiveness of telehealth ACT in supporting caregivers of children with AS.

Angelman syndrome (AS) is a neurogenetic condition marked by frequent smiling and laughter. Early descriptions portrayed these expressions as inappropriate or disconnected from context, but recent work has questioned this view. This study examined the emotional responses of children with AS to auditory, tactile, visual, and social stimuli and compared them to typically developing (TD) children and children with Autism Spectrum Disorder (ASD). Using Bayesian mixed-effects models, we analyzed behavioral ratings and Facial Action Coding System (FACS) data. Children with AS showed more frequent positive-expression behavior, but these elevations were selective rather than indiscriminate. All groups relied on a shared repertoire of smile- and laughter-related facial actions, with AS differing primarily in the intensity and frequency of these shared actions. These findings indicate that emotional expressions in AS are context-sensitive and grounded in meaningful environmental cues, challenging the notion that their positive affect is reflexive or aberrant.