Parents of children with Autism Spectrum Disorder (ASD) often exhibit subclinical autistic traits, known as the Broad Autism Phenotype (BAP). While BAP is recognized as a familial characteristic associated with ASD, limited evidence exists regarding how specific parental traits relate to children's behavioral, adaptive, and developmental outcomes in low- and middle-income clinical settings. Understanding these associations may be relevant for developmental and neurorehabilitation contexts in which parent - child interaction plays an important role in the child's learning environment. This descriptive cross-sectional study included 95 children (aged 2-12 years) newly diagnosed with ASD and both biological parents, recruited from a tertiary Child Development Center. Child autism severity was assessed using the Childhood Autism Rating Scale-2 (CARS-2); adaptive functioning using the Vineland Adaptive Behavior Scales - II (VABS-II); behavioral problems using the Child Behavior Checklist (CBCL); and developmental level using the Developmental Profile-3. Parental autistic traits were measured using the Autism-Spectrum Quotient (AQ). Correlation and regression analyses were used to examine associations between parental AQ traits and child outcomes. BAP (AQ ≥ 23) was present in 50% of mothers and 47% of fathers. Total parental AQ scores were not associated with child autism severity. However, higher parental communication-trait scores were associated with greater externalizing behavior in children (p < .05). Certain parental AQ subdomains, particularly communication and attention-to-detail traits, showed modest negative correlations with children's motor functioning and developmental level. In multivariable analysis, paternal communication traits remained independently associated with poorer motor skills (β =  -0.276, p = .034). Parental BAP traits, particularly those related to communication and social reciprocity, may be associated with variability in behavioral, motor, and developmental outcomes in children with ASD. Although parental traits were not associated with autism severity, these findings suggest that considering family phenotype may be relevant when examining child developmental profiles within family-centered neurodevelopmental and rehabilitation frameworks. Further longitudinal research is needed to clarify the nature and direction of these relationships. Provides data on BAP traits among Indian parents of children with ASD.Parental communication traits linked to child behavior and developmentParental autistic traits correlate with child motor and adaptive outcomesHighlights cultural influences on BAP expression in LMIC clinical settingsSuggests potential value of considering family phenotype in neurorehabilitation planning.
Computerized cognitive training (CCT) is increasingly used in pediatric rehabilitation; however, its application across developmental disorders remains heterogeneous in terms of targets, delivery models, and outcomes. This scoping review aimed to map the currently available CCT tools used in children with developmental disorders and to summarize their main characteristics, clinical targets, and evidence gaps. We conducted a scoping review in accordance with the PRISMA-ScR framework and registered the protocol on the Open Science Framework (OSF; DOI 10.17605/OSF.IO/9XQ5H). We searched peer-reviewed studies investigating CCT in children with developmental disorders and extracted data on device characteristics, target domains, training modalities, study design, and main findings. Twenty-two studies describing 21 devices were included. Evidence was heterogeneous across diagnoses, intervention architectures, comparators, and outcome measures. The most consistent signal emerged in ADHD, where some programs reported improvements in working memory and selected executive-function outcomes. Evidence in learning-related and intellectual developmental conditions was more variable and device-specific, while the only ASD study identified did not show superiority over mock training. CCT appears clinically attractive because of its adaptability, gamified delivery, and potential for home-based use; however, the current evidence base is uneven and does not support broad efficacy claims across developmental disorders. More disorder-specific studies with stronger comparators and ecologically valid outcomes are needed. https://osf.io/9xq5h, doi: 10.17605/OSF.IO/9XQ5H.
Developmental dyslexia is a specific learning disability for which early identification and intervention are crucial. In alphabetic languages, phonological awareness and letter naming are well-established early markers of reading disorders. For developmental dyslexia in Chinese, a language that differs from alphabetic languages in multiple aspects, little is known about its early markers. Here, we report findings from a 2.5-year longitudinal behavioral study and a functional neuroimaging study designed to identify the neural underpinnings of predictors of Chinese reading disability. In Experiment 1, 237 Chinese children were assessed at age 5 on phonological awareness, morphological awareness, phonological memory (measured by digit span) and rapid automatized naming (RAN). Their reading performance was measured two and a half years later using a nationally standardized Chinese reading assessment. Forty children were identified as dyslexic and fifty-six as typical readers. For the two groups of children, we found that phonological memory and RAN were unique and reliable predictors of reading disorders, explaining significant variance after controlling for other factors. The analyses with all 237 participants showed the same pattern. In Experiment 2, we conducted a brain-wide association study in skilled readers to examine whether these two predictors were associated with activation in reading-related regions. We found that phonological memory and RAN were strongly associated with regions supporting Chinese reading. This research has demonstrated that phonological memory and RAN are early cognitive markers of Chinese dyslexia and, for the first time, has tried to pave the way for effective early intervention strategies for Chinese reading difficulties.
Wearable movement sensing has enormous potential to transform the field of neurorehabilitation and neural repair. This perspective paper discusses: (1) the case for wearable sensing as a compelling, scalable measurement tool, (2) moving from first generation to second generation research in wearable movement sensing, (3) the enormity in the potential range of use cases for wearable technology, and (4) challenges that lie ahead for moving from research space into clinical rehabilitation care. Wearable sensors, as a measurement tool, offer a data-rich avenue for measuring numerous dimensions of motor behavior in the clinic and in daily life, complementing other available tools. Second-generation research questions focus on determining how to quantify, for whom, when, and with what variable(s). Answering these second-generation questions requires substantial evidence at the individual use case level; we provide 1 exemplar variable and its evidence within stroke recovery and rehabilitation. Potential use cases for deployment of wearable movement sensors span developmental, acquired, and degenerative neurological conditions and variables extracted can be intended as digital biomarkers and/or digital clinical outcome assessments. As research progresses, we look forward to the translation of this measurement tool into routine clinical care and welcome implementation challenges related to readiness, approach, and presentation in the busy, complex, healthcare arena. Achieving the promise of wearable movement sensing will require extensive collaboration, as exemplified by Dr. Wolf, across research teams, disciplines, institutions, people with lived experience, and other stakeholders.
De novo KCNA3 variants cause a Developmental and Epileptic Encephalopathy (DEE). We describe a 14-year-old boy presenting with DEE and carrying a heterozygous de novo KCNA3 (NM_002232.4) variant (c.1433T>A, p.Val478Glu) and an inherited KCNQ3 (NM_004519.3) variant (c.1720C>T, p.Pro574Ser). Human dermal fibroblasts (HDFs) were isolated from the patient and an age-matched control. KCNA3 and KCNQ3 transcript levels were quantified by qRT-PCR, showing in patient-HDFs a reduction of 77% and 40%, respectively (p < 0.0001; p = 0.0002). Western blot confirmed decreased KCNA3 and KCNQ3 protein levels by 50% and 35%, respectively (p < 0.05). The contributing role of both variants supports the rationale for a channel-targeted treatment strategy.
暂无摘要（点击查看详情）
SRRM4 is an exclusively neural-expressed splicing-factor gene not yet associated with a monogenic condition. We sought to delineate movement disorders caused by SRRM4 variants. De novo splice-donor-site variants at position +2 of intron 5 of SRRM4 (c.464+2T>C, c.464+2T>A) occurred in three unrelated patients with dystonia and chorea. We present detailed phenotypic information on these individuals and characterize the effect of the splice-site alteration. Exome and genome sequencing were used to identify SRRM4 variants. To assess the consequence of a mutant +2 residue at the affected splice donor of SRRM4, we performed transcriptomic analyses using short-read and long-read RNA-sequencing in patient fibroblasts in which SRRM4 expression was induced by genome editing. Clinical presentations were characterized by infantile combined dystonic and choreatic syndromes or chorea-predominant disease. Studies in SRRM4 expression-activated cells revealed two variant-specific SRRM4-mRNA isoforms including one that was characterized by a 69-nucleotide in-frame insertion without creation of a premature termination codon, suggestive of a mechanism other than loss-of-function. Additionally, we uncovered altered splicing patterns of known SRRM4 downstream mRNA-substrates in patient cells compared to SRRM4 expression-activated control fibroblasts, such as a conserved AP1S2 microexon. AP1S2 is linked to a monogenic syndrome with abnormal movements and missplicing of its microexon is a well-established outcome in neural models of SRRM4 disruption. We conclude that the patients' phenotypes are caused by a previously undiagnosed SRRM4-related disorder, offering a basis for improved understanding of mechanistic convergence in genetic movement disorders and potential therapeutic targeting of the misregulated splicing events. © 2026 The Author(s). Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
This narrative conceptual review explores the neurobiological underpinnings of play behaviour across species, with an emphasis on how play affects brain development, social functioning, and cognitive outcomes from early life through aging. We synthesize current neuroscientific literature from animal and human studies, focusing on translational evidence involving specific brain regions (e.g., prefrontal cortex, amygdala, striatum), neurochemical systems (e.g., dopamine, opioids), and behavioral domains (e.g., executive function, emotional regulation, and social cognition). Studies are categorized by developmental stage and functional impact. Evidence from rodent models demonstrates the activation of distinct neural circuits during structured and spontaneous play (e.g., hide-and-seek, rough-and-tumble), with sex-specific differences in cortical and subcortical engagement. In humans, play emerges in infancy and supports neural plasticity, language development, and executive functioning. Later in life, playfulness correlates with cognitive resilience and may act as a protective factor against neurodegeneration. The review also highlights play-based rehabilitation approaches (e.g., sensory-motor therapy, LEGO®-based interventions, sports) with demonstrated neurological and psychosocial benefits. Play is a multidimensional, evolutionarily conserved behaviour that engages neurobiological systems critical to development and health. Although promising evidence supports play-based interventions, further research is needed to clarify mechanisms, optimize therapeutic use, and bridge species-specific findings in translational neuroscience.
To determine whether extending home-based rehabilitation beyond the mother-only model to include fathers and siblings is associated with improved developmental outcomes in infants with neuro-developmental delay (NDD) and maternal wellbeing in an urban low-resource setting. A prospective observational cohort study was conducted at two public neuro-developmental clinics in Bulawayo, Zimbabwe. Infants aged 3-6 months (N = 481) and their mothers were followed for 3 months across three naturally occurring caregiver participation groups: mother-only, mother-father and mother-father-sibling. Developmental outcomes were assessed using the Bayley Scales of Infant and Toddler Development, Third Edition (BSID-III), and maternal wellbeing was measured using Global Quality of Life (QoL) and Mental Health Check-In Visual Analogue Scales. Group differences were analysed using ANCOVA, repeated-measures ANCOVA and multiple linear regression adjusting for baseline scores. Infants in the mother-father-sibling group demonstrated significantly higher baseline-adjusted BSID-III cognitive scores at 3 months than the mother-only group (p < 0.05), with the largest effect observed in this group. Changes in language, motor, socioemotional, and adaptive domains followed the same direction but showed smaller and less consistent effects, with limited pairwise significance after adjustment. Maternal mental health improved significantly over time across groups, while QoL showed small but statistically significant gains only on repeated-measures analysis. Involving fathers and siblings in home-based rehabilitation was associated with selective cognitive gains in infants and better maternal mental health over 3 months. These findings provide preliminary support for the integration of father- and sibling-inclusive, family-centred rehabilitation models for paediatric neurorehabilitation in similar low- and middle-income settings.
To analyze the clinical manifestations and genotype of a child with You-Hoover-Fong syndrome (YHFS) to enhance clinical understanding of this disease. Clinical data of a child who visited the Department of Pediatric Neurorehabilitation of the Women's and Children's Hospital Affiliated to Xiamen University in March 2025 for global developmental delay was collected. Peripheral blood samples of the child and his parents were collected for chromosomal microarray analysis and whole exome sequencing (WES). Sanger sequencing was performed for parental validation, and candidate variant was assessed for pathogenicity. Clinical and genetic analyses were conducted based on the child's phenotype. A literature review was performed by retrieving previously reported cases of YHFS due to TELO2 gene variants. This study was approved by the Medical Ethics Committee of the Women's and Children's Hospital Affiliated to Xiamen University (Ethics No.: KY-2023-044-K02). The child was a 1-year-and-2-month-old male presenting with global developmental delay, encephalodysplasia, congenital heart disease and distinctive facial features. WES revealed that the child has harbored compound heterozygous variants of the TELO2 gene, namely c.1826G>A (p.Arg609His) and c.1514_1515delAG (p.Glu505Alafs21). Sanger sequencing confirmed that his mother carried a heterozygous c.1826G>A variant and his father carried a heterozygous c.1514_1515delAG variant. Based on the guidelines from the American College of Medical Genetics and Genomics (ACMG), both variants were classified as likely pathogenic (PM2_Supproting+PM3_Strong+PP1+PP3; PVS1+PM2_Supproting). Literature review has identified 9 articles reporting 31 cases of YHFS due to TELO2 gene variants, with primary clinical manifestations including developmental delay, intellectual disability, distinctive facial features, and congenital heart disease. The c.1826G>A (p.Arg609His) and c.1514_1515delAG (p.Glu505Alafs*21) compound heterozygous variants of the TELO2 gene probably underlay the pathogenesis of this child. Above finding has provided a basis for the clinical and genetic diagnosis of the child, which also enriched the mutational spectrum of the TELO2 gene, and improved understanding of YHFS.
In recent years, many robotic devices and technologies have been developed to support rehabilitation. These technologies have started penetrating clinical practice, and healthcare practitioners have started to be trained in their use, but only in selected healthcare environments. As a matter of fact, several barriers still exist for a wider dissemination of robotics-assisted rehabilitation, and little is known about the real needs of patients and their caregivers when they undertake a rehabilitation process. To address this issue a survey has been developed as a preparatory step for the effective use of robots and technologies in rehabilitation. The survey aims to identify and highlight patient's needs which are often unexpressed, enabling the co-creation of future rehabilitation solutions with patients and their caregivers. The methodology for developing the survey involves reaching out to as many people with neurological disorders as possible, understanding their needs in relation to specific functional areas, and using innovative methods such as online platforms to maximize outreach. Common functional domains for different neurological conditions were developed with a holistic view of people with disabilities, using the categories and domains defined by the new International Classification of Functioning, Disability and Health (ICF). Surveys addressed to patients, caregivers of adults and of children were developed by sharing the same content and exploring the rehabilitation carried out, both traditional and technological, with particular focus on the willingness to adopt technology, if not yet integrated in the current care. This approach aims to develop future rehabilitation strategies that utilize the increasing availability of neurorehabilitation technologies in a more effective and personalized way. This study highlights the importance of focusing on the fundamental role of addressing patients' needs in driving innovation and adoption of neurorehabilitation technologies, prior to clinical effectiveness. This is pivotal in identifying the specific desiderata, to co-create together with the end users new solutions to empower the patient-professional relationship and optimize the satisfaction related to the treatment and, as a consequence, the adherence to the intervention and its results.
Mirror movements are involuntary, task-coupled contractions in contralateral homologous muscles during unilateral movement. While often described as a developmental remnant or rare clinical sign, mirror movements offer insight into the physiological mechanisms that underlie motor lateralization and interhemispheric balance. This review aimed to synthesize the available neurophysiological evidence-primarily from transcranial magnetic stimulation (TMS)-and propose a structured, mechanism-based framework for interpreting mirror movements across neurological conditions. A structured narrative review was conducted of studies published between 1966 and November 2025 using TMS in individuals with congenital, developmental, or acquired mirror movements. Studies using neuroimaging or peripheral electrophysiology were included selectively to support anatomical or functional interpretation of TMS findings. Data were organized into three mechanistic layers based on prevailing neurophysiological signatures rather than etiology alone. Three non-mutually exclusive mechanisms were identified: (I) persistent fast-conducting ipsilateral corticospinal projections, primarily in congenital mirror movement syndromes and early brain injury; (II) deficient transcallosal inhibition, observed in conditions affecting interhemispheric balance such as amyotrophic lateral sclerosis, multiple sclerosis, Parkinson's disease, and callosal agenesis; and (III) bilateral overactivation of premotor and supplementary motor areas, especially under conditions of impaired motor program selection or increased task demands. Mirror movements can be interpreted within a tri-layer model reflecting distinct disruptions in corticospinal connectivity, interhemispheric inhibition, and supraspinal motor control. This framework provides an integrative model for interpreting neurophysiological findings in mirror movements, offering insight into hierarchical motor control without implying specific diagnostic or therapeutic applications.
Pediatric neurological disorders comprise a highly heterogeneous group of conditions that together represent a substantial global public health burden. Many have a strong genetic basis and are associated with significant morbidity, premature mortality, and long-term disability, with far-reaching consequences for affected children, their families, and healthcare systems worldwide. Clinical heterogeneity is a hallmark of these disorders, as pathogenic variants in the same gene can give rise to diverse phenotypes with variable severity, age at onset, and disease course. In children, ongoing brain development and somatic growth further complicate diagnosis, often leading to nonspecific or atypical presentations that differ from classical adult neurological phenotypes. Advances in genetics and genomics have fundamentally transformed the understanding, diagnosis, and classification of pediatric neurological diseases. The widespread use of high-throughput sequencing, genome-wide association studies, and integrative bioinformatics approaches has enabled the rapid and precise identification of disease-associated genes, even in sporadic and complex conditions, facilitating earlier and more accurate diagnoses and highlighting the role of genetic background and gene-environment interactions in disease pathogenesis. Here we provide an overview of the genetic and genomic landscape of key pediatric neurological disorders with well-characterized molecular etiologies, including neuromuscular disorders, epilepsies, neurodevelopmental disorders, neurodegenerative diseases, and movement disorders. Current knowledge is synthesized with emphasis on clinical presentation, genetic architecture, and genotype-phenotype correlations. Gene-specific management strategies and emerging precision therapies are discussed for selected conditions, underscoring the central role of genetic diagnosis in guiding clinical decision-making and improving outcomes in affected children.
Cerebral palsy (CP) is the most common cause of disability in developmental age, affecting motor and postural skills. With growth, lower-limb orthopedic surgery often becomes necessary. Post-surgical walking rehabilitation programs generally involve conventional therapy with only limited evidence on the use of robot-assisted gait training (RAGT). The aim of the present pilot study is to assess the feasibility and the preliminary functional outcomes of an intensive 3-week rehabilitation of 15 sessions with Lokomat combined with 15 sessions of conventional physiotherapy. In total, 27 patients with diplegic cerebral palsy who underwent orthopedic surgery were recruited. Outcomes collected: the 6 min walking test (primary outcome), the Gross Motor Function Measure-88, the Gillette Functional Assessment Questionnaire, 3D gait analysis, and spasticity and force metrics of the lower limbs. Paired statistical tests were used to assess pre-post changes. A pre-post statistically significant improvement was observed in gait endurance in the 6MWT (Δ = 28.56 ± 34.28 m; p < 0.001) and in gross motor functional skills. Gait parameters showed some functional and structural improvements, and joint stiffness was reduced in some measures. This combined rehabilitative approach seems to be promising in postoperative patients with CP. Future studies, involving a control group and larger sample size, are needed to generalize our results.
Children with cerebral palsy often experience persistent upper extremity impairments that impact independence and participation in daily activities. Wearable neurotechnology devices offer a promising, non-invasive approach to enhance motor control, promote neuroplasticity, and extend neurorehabilitation beyond clinical settings. However, the development and application of such devices in pediatric populations remains poorly defined. This scoping review aimed to map the existing literature on wearable neurotechnology systems used for upper extremity rehabilitation in children with cerebral palsy and identify knowledge gaps to guide future research and clinical translation in pediatric neurorehabilitation. This review followed the JBI Scoping Review Methodology and PRISMA-ScR guidelines. Four electronic database sources, MEDLINE, Scopus, CINAHL, and PsycINFO, were systematically searched to identify studies on wearable neurotechnology devices for upper extremity rehabilitation in children with cerebral palsy. Included studies consisted of journal articles published from January 2005 to June 2025, with full texts available in English and relevant gray literature sources. Data were extracted on neurotechnology characteristics, regulatory status, intervention protocols, and outcome measures. From the 2,892 articles screened, 21 met the eligibility criteria. Most devices were in early developmental stages, with only five receiving regulatory approval. Studies examined various systems, including electromyography-triggered stimulation, virtual reality, and robot-assisted devices with haptic or electrical stimulation, and wearable garments embedded with electrical or vibrotactile stimulators. Intervention protocols varied widely across studies in terms of treatment intensity, wear schedules, and co-interventions. Feasibility was generally positive across studies, with high adherence rates and minimal adverse events reported. Many studies reported improvements in motor outcomes, including enhanced grip strength, hand use, range of motion, grasp and release ability, and muscular recruitment. Wearable neurotechnology shows potential to augment upper extremity rehabilitation in children with cerebral palsy, particularly through systems that support task-specific, feedback-driven practice. However, translation to clinical practice is limited by heterogeneity in device design, lack of standardized protocols, and limited high-quality evidence. Future research should prioritize standardization, clinician-centered implementation studies, and long-term outcomes to support integration into pediatric care. https://osf.io/5qxpe.
Although subtle differences in cortico-striato-thalamo-cortical (CTSC) circuit structure and function are critical to the current understanding of the neurocircuitry in obsessive-compulsive disorder (OCD), emerging evidence suggests that the cerebellum may also be involved. However, much of this evidence comes from studies with small samples and notable methodological heterogeneity. We conducted a mega-analysis of individual participant data on cerebellar sub-regional volumes, comparing individuals with OCD and healthy controls (HC) from the ENIGMA-OCD Working Group. 3D T1-weighted volumetric structural brain magnetic resonance imaging (MRI) scans from 1,954 individuals with OCD and 2,091 HC across 22 sites (40 datasets) were processed using the ACAPULCO (Automatic Cerebellum Anatomical Parcellation using U-Net Locally Constrained Optimization) pipeline to extract cerebellar parcellations. We harmonized the volume measures across sites using the ComBat algorithm. Multiple linear regression models were fitted to estimate group differences separately within the pediatric (<12 years), adolescent (12-18 years), and adult (from 18 years) samples, adjusting for age, gender, and intracranial volume (ICV). In adults with OCD (versus HC), we found significantly smaller volumes of the corpus medullare (d=-0.093, pfdr=0.036), left VIIb (d=-0.085, pfdr=0.039) and right VIIb (d= -0.091, pfdr= 0.036). None of the comparisons between children or adolescents with OCD versus HC remained statistically significant after FDR correction. In all three age groups, cerebellar (subregional) volumes were significantly moderated by medication status. We report novel findings implicating specific cerebellar sub-regions across developmental stages of OCD, and the key impact of medication status. Further research on the functional significance of these findings may offer new translational leads.
Children with Down syndrome (DS) experience delays across multiple developmental domains, including communication and motor coordination. While prior studies have investigated these domains separately, few have examined their interrelation using population-level data. This study aimed to evaluate (1) differences between young children with DS and typically developing (TD) peers in early communication skills and motor-coordination difficulties, and (2) whether the relationship between these domains is similar across groups. This brief report used data from the 2021-2022 National Survey of Children's Health, a nationally representative U.S. dataset including children aged 0-5 years. Children were categorized as having DS (parent-reported diagnosis) or typical development (no developmental delays). Early communication skills were assessed using 11 parent-report items (five receptive, six expressive). Motor coordination was assessed using two items reflecting chronic difficulty using hands or moving around. Chi-square tests were used to compare group differences and to examine associations between motor coordination and communication milestones within each group. The sample included 90 children with DS and 24,988 TD children. Compared with TD peers, children with DS were less likely to achieve all early communication milestones and more likely to experience motor-coordination difficulties (p < .001). Within the DS group, those with motor-coordination difficulties were less likely to say one word (57.1% vs 80.6%), follow verbal directions (45.2% vs 72.2%), point to things (38.1% vs 69.4%), understand "in," "on," "under" (31.0% vs 58.3%), or use two words (19.0% vs 44.4%) compared to TD children (p < .05). The TD group showed significant associations between the acquisition of early communication skills and motor coordination difficulties for all the early communication skills recorded (p < .01). Findings indicate a dynamic, bidirectional relationship between early motor coordination and communication skill acquisition in young children with DS, mirroring patterns observed in TD peers. Population-level evidence underscores the need for early interventions targeting both domains concurrently. Future prospective studies using standardized developmental assessments are warranted to clarify temporal relationships and inform early intervention strategies.
Pathogenic variants in γ-aminobutyric acid type A (GABAA) receptor genes have been associated with a wide spectrum of neurological disorders. We aimed to delineate the clinical trajectories associated with gain-of-function (GoF) and loss-of-function (LoF) variants in GABRB2 and GABRB3, and to develop a risk-prediction model for gross motor dysfunction based on age at seizure onset. Clinical data, including seizure onset, epilepsy syndromes, cognitive outcomes, and gross motor function classification system (GMFCS), were collected through direct interviews, physician reports, and literature review. Kruskal-Wallis, Mantel-Cox and non-parametric analysis of variance (ANOVA) with Dunn's corrected post hoc tests were used for statistical comparisons. A logistic ordinal regression model was developed to predict GMFCS outcomes based on age at seizure onset. We analyzed a cohort of 117 individuals with pathogenic GABRB2 (n = 49) and GABRB3 (n = 68) variants. Fifty-three individuals carried GoF variants and 64 carried LoF variants. The GoF group was associated with earlier seizure onset, higher seizure frequency, and lower rates of seizure freedom. Gross motor dysfunction was markedly worse in the GoF group, with 64% classified as GMFCS IV or V (non-ambulation), compared to 7.5% in the LoF group. An inverse correlation was found between age at seizure onset and GMFCS severity in the GoF, but not the LOF group. The risk model predicted a >90% likelihood of non-ambulation for individuals with GoF variants and seizure onset before 1 month of age, decreasing to ~35% with seizure onset after 20 months. We found a clear genotype-phenotype correlation in GABRB2- and GABRB3-related disorders, demonstrating that GoF variants are associated with a more severe neurodevelopmental trajectory. The age at seizure onset serves as a biomarker for predicting motor outcomes in individuals with GoF variants. These findings provide guidance regarding prognosis, need for early intervention, and data for comparison of efficacy in targeted therapeutic interventions for GABAA receptor-related disorders.
Angelman syndrome (AS) is a rare and heterogeneous genetic disorder characterized by intellectual and psychomotor delay, speech deficits, seizures and behavioural issues. To evaluate the feasibility of collecting data by many Italian centers involved in pathology management, and to investigate the relationship between various symptoms and genotypes, a dedicated AS registry was developed. This study aims to present preliminary findings from the Italian AS registry (IReAS), with a specific focus on exploring genotype-phenotype correlations. The IReAS, established in 2020, aims to collect information from 14 different Italian referral. It includes demography, diagnosis and genetic, patient status, therapeutic interventions and mortality data collection. 213 patients (55.4 % female vs 44.6 % male) were included in the IReAS during the 2020-24 period. Average age at genetic diagnosis was 3.8 years; 63 % of patients was paediatric; 70.4 % of subjects had maternal deletion. Most patients exhibited global developmental delay (100 %), movement disorders (94.8 %), behavioral abnormalities (96.2 %), and a total lack of language development (95.8 %). Epilepsy is also highly prevalent (80.3 %), with a significantly higher incidence in patients with maternal deletion compared to non-deletion groups (88 % vs 61.9 %). The IReAS provides comprehensive data on the diagnosis, genetic subtypes and clinical features of AS patients. It can facilitate genotype-phenotype correlation analyses, offering insights into the AS natural history and potential implications for research on targeted therapies.
Lennox-Gastaut syndrome (LGS) is one of the most severe, yet one of the most discussed, childhood-onset developmental and epileptic encephalopathies (DEEs). Dissent among epileptologists on the definition and minimum set of electroclinical features derives from the high etiological heterogeneity within the syndrome, which could make its prevalence overestimated. However, in recent years, our diagnostic strategies, including both high-resolution magnetic resonance imaging and next-generation sequencing techniques, have enabled us to disentangle many cases previously classified as "idiopathic." In addition, some electroencephalographic and circulating biomarkers have been identified that could predict disease progression and treatment response if confirmed in larger patient populations. As our diagnostic capacity increases, so do our treatment strategies. Although progress has been made, the implementation of better clinical trial designs, individualized treatments, and therapies that address the genetic roots of the disease remains necessary in clinical practice. A lot is being done in this direction, thanks to the involvement of families and the creation of international networks, such as the ERNs, which are rapidly promoting collaboration among highly specialized centers and the establishment of disease registries to shed light on the natural history of LGS. Yet, many unmet needs still afflict patients and their families, including uncertainties arising from the transition process and a lack of administrative support and comprehensive care as patients transition into adulthood. This article summarizes these key challenges in diagnosing, treating, and caring for patients with LGS, as well as the roadmap to enhanced future care discussed during the international LGS meeting held in Genoa.