Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by multiple neurological impairments, which affects predominantly females. It is associated, in most cases, with pathogenic variants in MECP2, the gene encoding the methyl-CpG-binding protein 2. In the four decades since its description in the English literature, the RTT field has seen major progress in the understanding of its genetics, neurobiology, and clinical evolution. These have led to the first drug approved for core symptoms of a neurodevelopmental disorder, trofinetide, and gene replacement programs at advanced development. These achievements have brought new challenges and highlighted unresolved issues. These include diagnosis before developmental regression and of individuals without core RTT features, including males; the role of MECP2 testing in RTT diagnosis; the boundaries of RTT; instruments needed for assessing clinical evolution in research and practice; the definition of meaningful clinical improvement; and the development, availability, and affordability of new treatments. These topics are reviewed in terms of their implications for RTT and for other genetic neurodevelopmental disorders.
AIM:To describe the patterns of co-occurrence between previously documented risk factors and gestational age in infants with cerebral palsy (CP) registered in the Argentine Cerebral Palsy Register (Registro Argentino De Parálisis Cerebral [RAR-PC]). METHOD:This register-based, cross-sectional study analysed data from individuals with confirmed CP registered in the RAR-PC. Family interviews and medical record reviews were conducted. The variables analysed included CP characteristics, a predefined set of prenatal, perinatal, and postnatal risk factors, and sociodemographic variables. Correspondence analysis was used to identify patterns of co-occurrence between these risk factors and gestational age at birth. RESULTS:Three hundred individuals born preterm and 196 individuals born at term with CP were included in this study. Prenatal risk factors that co-occurred with preterm birth included low birthweight, neonatal respiratory disease, prolonged hospitalization, and family circumstances such as critical overcrowding and an unemployed primary income earner. In contrast, term births were more frequently accompanied by home delivery, incomplete antenatal care, and family circumstances such as critical overcrowding and an unemployed primary income earner. Infants born preterm were often presented simultaneously with admission to a neonatal intensive care unit or special care nursery, whereas infants born at term tended to co-occur with perinatal asphyxia and feeding difficulties. INTERPRETATION:Risk factors for CP, previously documented and systematically collected according to the directives of the Global Low and Middle Income Cerebral Palsy Register, co-occur differently with gestational age. These locally specific patterns provide relevant guidance for prevention, early diagnosis, and tailored interventions.
AIM:To assess the causal pathway between preterm birth and infant neurodevelopmental delay, with maternal depression as the mediator using a counterfactual mediation framework. METHOD:A prospective cohort of 1253 mother-infant pairs were enrolled and followed up until 6 months in Nepal. Preterm birth was assessed using medical birth register; maternal depression and infant neurodevelopmental delay were assessed using maternal interview. Causal mediation analysis was performed using logistic regression models using the R mediation package, estimating average causal mediation effect (ACME), average direct effect, total effect, and proportion mediated. Model diagnostics included multicollinearity, goodness-of-fit, influential observations, and positivity. RESULTS:Preterm birth was associated with increased odds of infant neurodevelopmental delay (total effect odds ratio [OR] = 1.12, 95% confidence interval [CI]: 1.06, 1.18). Maternal depression symptoms partially mediated this association (ACME OR = 1.04, 95% CI: 1.02, 1.07), with a direct effect of preterm birth remaining significant (average direct effect OR = 1.07, 95% CI: 1.02, 1.13). Approximately 38% of the total effect was mediated by persistent maternal depression. Sensitivity analyses indicated moderate robustness to unmeasured confounding. INTERPRETATION:Maternal depression is an important pathway linking preterm birth to infant neurodevelopmental delay, though additional direct mechanisms exist. Interventions targeting maternal mental health may partially mitigate the developmental risks associated with preterm birth.
AIM:To map factors related to employment in adults with cerebral palsy (CP), summarize evidence on barriers and facilitators, and identify gaps in existing literature. METHOD:A scoping review was conducted in accordance with the JBI. A systematic search across five databases up to 22nd March 2026 identified 29 studies including 33 069 adults with CP. The outcome of interest was paid employment and employment dropout in adults with CP. Factors were categorized using the International Classification of Functioning, Disability and Health (ICF) framework. RESULTS:Twenty-one studies addressed body functions and structures (e.g. intelligence, dexterity), 11 focused on activities (e.g. Gross Motor Function Classification System level, independence), five on participation (e.g. communication), 13 on environmental factors (e.g. accessibility, support), and 20 on personal factors (e.g. age, education). Methodological quality varied, with many studies rated low to moderate. INTERPRETATION:Employment among adults with CP is shaped by interrelated factors across ICF domains. Research gaps include limited attention to environmental and personal factors, underrepresentation of adults over 40 years of age, and lack of longitudinal studies. Addressing these gaps and learning from other populations is essential to improve vocational support.
AIM:To investigate the efficacy of the Hand-Arm Bimanual Intensive Therapy Including Lower Extremities (HABIT-ILE) compared with usual physiotherapy delivered at the same dosage in children with bilateral cerebral palsy (CP) in Benin. METHOD:This randomized controlled trial involved 32 children (19 males, 13 females) with bilateral CP, aged 2 to 4 years, classified in Gross Motor Function Classification System levels III and IV, randomly allocated to HABIT-ILE or a high-dosage physiotherapy group. Interventions were delivered at a 2-week camp. Children were assessed before and after interventions and at the 2-month follow-up using the Gross Motor Function Measure (GMFM), the Both Hands Assessment (BoHA), the Canadian Occupational Performance Measure (COPM), and the Activity Limitations Questionnaire, West African version (ACTIVLIM-CP-WA). RESULTS:A significant group × testing time interaction indicated a significant improvement in GMFM scores after HABIT-ILE, which was sustained at the follow-up. Children in the usual physiotherapy group improved slightly at the follow-up. No significant changes in BoHA were observed in either group. Both groups improved in COPM scores, with a larger improvement after HABIT-ILE. The ACTIVLIM-CP-WA measures improved over time with no group differences. INTERPRETATION:HABIT-ILE is more efficacious in improving motor and functional outcomes in children with bilateral CP than usual physiotherapy administered at the same dosage, demonstrating the importance of therapy content.
AIM:To investigate the presence of accelerated long-term forgetting after a 7-day delay in children with neurofibromatosis type 1 (NF1), using an adapted verbal memory recall task, Experimental Word Recall Task (EWRT), and to examine its relationship with other cognitive abilities. METHOD:This cross-sectional design involved 60 children with NF1 and 88 typically developing children who completed the EWRT and were aged between 6 years and 15 years 11 months. Statistical analyses were carried out in individuals who met the EWRT learning criteria (i.e., were able to successfully learn the list of words during the learning phase; NF1, n = 40, 19 females; typically developing, n = 84, 44 females). The EWRT was used to investigate accelerated long-term forgetting across delays of 2 and 30 minutes, and 7 days. Correlational analyses were used to examine the relationships between accelerated long-term forgetting and other cognitive measures in children with NF1. RESULTS:In the subset of children who were able to learn the EWRT criterion, there was no group difference in recall performance at a traditional delay interval of 30 minutes. Group differences were evident at a 7-day interval for recall and recognition. In children with NF1, this long-term forgetting (difference in proportion of recall between 7 days and 30 minutes) was not significantly associated with attention or working memory difficulties. INTERPRETATION:The study suggests that children with NF1 who can initially learn verbal information and retain it over a short delay of 30 minutes may forget this information at an accelerated rate compared to their unaffected peers. Findings may account for the reported subjective memory difficulties in children with NF1 despite normal performance on standardized memory tests. This insight challenges conventional perspectives on memory in children with NF1 and emphasizes the importance of extending assessment timelines beyond traditional boundaries.
AIM:To systematically review the effectiveness, safety, and economic evidence of pharmacological and non-pharmacological interventions for sleep disorders in children with cerebral palsy (CP). METHOD:Databases including MEDLINE, Embase, CENTRAL (the Cochrane Library), International Clinical Trials Registry Platform of the World Health Organization, NHS Economic Evaluation Database, and ClinicalTrials.gov were searched up to May 2026. Randomized controlled trials and economic evaluations were eligible. Primary outcomes included sleep quality, adverse events, and tolerability. We incorporated interest holder perspectives, including clinicians and individuals with lived experience, throughout outcome prioritization and interpretation. We assessed risk of bias using the Cochrane Risk of Bias 2.0 tool and evaluated the certainty of evidence using Grades of Recommendation, Assessment, Development and Evaluation. RESULTS:Twelve randomized controlled trials (n = 19-142, aged 5-17 years) were included. Pharmacological (melatonin, cannabis-based medicines, baclofen, neural stem cells) and non-pharmacological interventions (massage, cranial osteopathy, music therapy, acupuncture, postural support) were evaluated. Melatonin improved sleep latency and duration modestly compared with placebo. Other interventions showed inconsistent or negligible effects. Adverse events were mild and tolerability acceptable. No completed economic evaluations were identified. Interest holders highlighted the multifactorial nature of sleep problems, the need for interventions addressing comorbidities, and improved reporting of equity factors. INTERPRETATION:Evidence for managing sleep disorders in children with CP is limited, heterogeneous, and of low certainty. Robust trials and economic evaluations are urgently needed.
AIM:To develop the Pediatric Autoimmune encephalitis Severity Scale (PASS) using expert consensus and the Delphi process, and validate it in children with autoimmune encephalitis. METHOD:This prospective observational study enrolled children who underwent serial rating with PASS, the Clinical Assessment Scale in Autoimmune Encephalitis (CASE), and the modified Rankin Scale, at eight time points until 6 months of presentation. Clinical outcomes included the Pediatric Quality of Life Inventory (PedsQL) score (parent-rated) and developmental and intellectual outcome at 6 months. Interrater agreement, internal consistency, and correlations of PASS and CASE with clinical outcomes were compared. RESULTS:There were 361 assessments in 27 children (11 females, 16 males) with autoimmune encephalitis (15 with antibody-negative autoimmune encephalitis, 11 with N-methyl-D-aspartate receptor antibody encephalitis, and one with steroid-responsive encephalopathy associated with autoimmune thyroiditis) with a median age at onset of 4 years (interquartile range = 3 years to 6 years 5 months). There was excellent interrater agreement for PASS and CASE with comparable intraclass correlation coefficients (0.984 vs 0.983). The worst PASS score was inversely correlated with the final PedsQL score (r = -0.42, p = 0.047). Factor analysis revealed distinct 'cognitive and behavioural' and 'disinhibition and excitability' dimensions in the PASS items. INTERPRETATION:PASS is a severity assessment tool for autoimmune encephalitis in children and offers an alternative to adult scales, which may be difficult to use in children.
Developmental and/or epileptic encephalopathy with spike-wave activation in sleep is a childhood epileptic encephalopathy spectrum where sleep-related spike-wave discharges drive neurocognitive regression during critical developmental periods. This narrative review synthesizes current evidence on underlying mechanisms and presents an updated diagnostic framework. Impaired slow-wave activity downscaling and sleep spindle disruption predict neurocognitive outcomes more robustly than spike-wave index alone, with thalamic integrity emerging as an independent prognostic marker. Genetic diagnoses have been identified in up to 55% of cases, with GRIN2A variants the most common monogenic aetiology. A structured review of published articles detailing 293 individuals confirmed that language, cognitive, and behavioural impairments frequently coincided with, or sometimes occurred independently of, seizure onset. Our proposed diagnostic framework integrates sleep electroencephalogram-prioritizing spindle preservation and slow-wave organization-alongside high-resolution magnetic resonance imaging, trio-based genomic sequencing, and longitudinal neuropsychological assessment. Further research is needed to validate sleep-based biomarkers and determine whether early intervention improves neurodevelopmental outcomes.
AIM:To identify shared and disorder-specific molecular alterations across encephalitis, Aicardi-Goutières syndrome (AGS), and autism spectrum disorder (ASD) using cerebrospinal fluid (CSF) proteomics. METHOD:In this cross-sectional case-control study, mass-spectrometry-based proteomics was performed on archived CSF samples collected between 2016 and 2019 from children with encephalitis (n = 15, nine males, mean age 8 years 2 months, SD 3 years 8 months, range 2-13 years), genetically confirmed AGS (n = 7, five males, mean age 5 years 4 months, SD 4 years 5 months, range 1 year 10 months-14 years), and ASD (n = 10, 10 males, mean age 7 years 2 months, SD 4 years 4 months, range 2-15 years). Each cohort was compared with age-matched and sex-matched non-inflammatory neurological disorder controls. Differentially abundant proteins (false discovery rate [FDR] < 0.05) and enriched pathways were identified using Reactome. Selected proteins were validated using targeted mass spectrometry (selected reaction monitoring or high-resolution multiple reaction monitoring). RESULTS:Encephalitis showed increased immunoglobulin and acute-phase proteins, with reduced glycolysis, synaptic, and extracellular matrix proteins. AGS demonstrated increased interferon signalling, Toll-like receptor pathways, and synaptic proteins, with reduced neural structural and extracellular matrix proteins. ASD exhibited increased extracellular matrix organization and oxidative protection proteins, with decreased haemostatic and stress response proteins. Complement and innate immune pathways were enriched across all cohorts, with increased abundance of C1S, C1R, CFH, and C4A. INTERPRETATION:This hypothesis-generating study shows shared complement activation across encephalitis, AGS, and ASD, which suggests complement dysregulation as a common neuroimmune mechanism and potential biomarker in childhood neuroinflammation.
