Annals of Clinical and Translational Neurology

BackgroundPreterm birth is associated with an increased risk for neurodevelopmental impairments, requiring brain monitoring using amplitude-integrated electroencephalography (aEEG). While established tools detect severe dysfunction (e.g., Hellstrom-Westas classification), methods for assessing mild to moderate impairments--such as Burdjalov scoring or expert-based Sleep-Wake Cycle identification--are subjective and require specialized training. Automated neonatal sleep-staging models usually rely on polysomnography from term infants, a resource-intensive method rarely feasible in NICUs, where simplified single-channel aEEG is standard. MethodsaEEG recordings from 40 neurologically healthy neonates (32-42 weeks PMA) were collected and annotated for quiet (QS) and non-quiet sleep (NQS) by an expert clinician. Signals were bandpass filtered, segmented into 30 s epochs, and cleaned using impedance thresholds. 69 temporal, spectral, wavelet, EMG-inspired, and aEEG-envelope features were extracted. The 5 most relevant features were selected for QS/NQS classification using several machine-learning models validated with leave-one-subject-out cross-validation. A partial least squares model was then trained on QS-derived features to predict postmenstrual age and assess correlations with brain maturation. ResultsThe k-Nearest Neighbors (KNN) classifier showed the best QS/NQS discrimination, with mean Cohens{kappa} = 0.69 {+/-} 0.14 for preterm (32-37 weeks PMA) and 0.48 {+/-} 0.21 for term infants. QS-derived features correlated strongly with postmenstrual age (PMA). The PLS model predicted PMA with an average error of 0.88 weeks (MSE = 1.33 weeks, r = 0.91), while the fully automated version using predicted QS segments yielded an error of 1.08 weeks (r = 0.86). ConclusionAutomated QS/NQS detection from single-channel aEEG is feasible in preterm neonates. Despite reduced accuracy in term infants, QS-derived features closely track brain maturation, supporting the potential of aEEG-based models for objective, early detection of neuromaturation delays in preterm infants

Adenylosuccinate synthetase 1 (ADSS1) myopathy is an ultra-rare disease characterized by progressive muscle dysfunction. The objective of this investigation was to employ a non-invasive biomarker approach to phenotype (fine-)motor skills, speech production and cognition in adults with ADSS1 myopathy. Five individuals with ADSS1 myopathy and five age-sex-matched healthy controls (HCs) underwent a comprehensive multimodal evaluation. Assessments included, (i) evaluation of motor performance, (ii) speech production and cognitive test batteries, (iii) patient-reported outcomes, (iv) electrical impedance myography (EIM), (v) musculoskeletal magnetic resonance imaging (MRI) and (vi) plasma proteomics. ADSS1 participants vs. HCs demonstrated reduced performance on the 9-Hole Peg and grip strength tests as well as lower self-reported mobility. Speech production analysis revealed asthenia (p=0.02), lower intelligibility (p=0.008), and worse voice quality during the sustained vowel task (p=0.03) in the ADSS1 cohort. Cognitive functioning remained unaffected in patients with ADSS1. On EIM, ADSS1 participants vs. HCs, demonstrated a pattern of higher resistance and lower reactance and phase across upper- and lower-extremity measurements, indicative of poorer muscle health, with large effect sizes (Cliffs 8=0.5-0.9). MRI revealed intramuscular fat infiltration, particularly in posterior compartments of the upper leg (e.g., biceps femoris). Proteomics indicated reduced (p=0.04) Neurotrophin-3 (NTF3; implicated in neuronal development, survival and differentiation) levels in the ADSS1 cohort relative to HCs. Lower NTF3 levels associated with poorer performance on hand-motor tasks as well as higher resistance and lower reactance and phase on EIM. This study highlighted the value of multimodal phenotyping for quantifying disease expression and advancing monitoring strategies in ADSS1 myopathy. Take-home messageThis multimodal investigation demonstrates that integrating electrical impedance myography with quantitative motor, speech, musculoskeletal imaging, and proteomic assessments provides a sensitive and non-invasive research framework for capturing neuromuscular dysfunction and functional disease burden in patients with ADSS1 myopathy, thereby supporting the current biomarker strategy for refined phenotyping and longitudinal disease monitoring in this ultra-rare condition.

Background Friedreich ataxia (FRDA) is a rare neurodegenerative disorder with substantial heterogeneity in clinical presentation and progression, complicating prognosis and trial design. Neuroimaging offers objective biomarkers to track disease evolution, yet variability in progression patterns remains poorly understood. Objective To identify biologically meaningful FRDA progression subtypes using longitudinal multimodal MRI and assess their associations with demographic, genetic, and clinical factors. Methods Longitudinal structural and diffusion MRI data from 54 FRDA and 57 controls were analysed. Annualised progression rates of macrostructural (volumetric) and microstructural (diffusion) features across cerebellum, brainstem, and spinal cord regions were clustered using Gaussian Mixture Models. Cluster robustness was assessed using per-cluster Jaccard similarity and other validation metrics. Random Forest classification examined predictors of cluster membership. Results Three reproducible clusters/subtypes emerged: micro-dominant/dual progression, characterised by widespread microstructural deterioration with modest volumetric decline; macro-dominant, marked by pronounced volumetric decline with minimal microstructural change; and minimal/no progression, showing negligible change in all measures. FRDA participants predominated in the first two clusters. Random Forest prediction of cluster membership using clinical and demographic variables identified length of the trinucleotide repeat expansion in the FXN gene as key predictor. Conclusions Data-driven clustering of longitudinal MRI identified distinct FRDA subtypes with unique co-progression patterns, underscoring genetic burden as a key driver. Recognising such heterogeneity can improve patient stratification, enable personalised monitoring, and guide targeted therapeutic strategies. Future studies should validate these subtypes in larger, more diverse cohorts and integrate additional biomarkers for enhanced precision.

BackgroundDopa-responsive dystonia is caused by pathogenic variants in the GCH1 gene. Although its clinical features and reduced penetrance are known, in vivo metabolic and structural alterations in symptomatic (sMC) and asymptomatic mutation carriers (aMC) remain poorly understood. ObjectivesTo characterize volumetric and neurometabolic brain changes of GCH1 mutation carriers and explore their relationship with clinical severity. MethodsWe studied 20 sMC, 5 aMC, and 25 mutation-free healthy controls (HC) using volumetric MRI combined with 31phosphorus magnetic resonance spectroscopy imaging (31P-MRSI) of the basal ganglia and cerebellum. ANCOVA was used for group comparisons, and correlations were assessed with clinical symptom severity rating scales. ResultsVolumetric analyses revealed enlarged globus pallidus (+16.6%, p = 0.001) and putamen (+7.2%, p = 0.031) volumes in carriers and increased cerebellar gray matter in aMC (+8.0%, p = 0.050). NAD levels were significantly reduced in the basal ganglia of carriers (NAD/Pi: -14.7%, p = 0.046; NAD/ATP-: -15.5%, p = 0.018). In the cerebellum, aMC demonstrated elevated high-energy phosphate ratios ((ATP-+PCr)/Pi: +23.7%, p = 0.017; ATP-/Pi: +21.3%, p = 0.046; PCr/Pi: +25.2%, p = 0.009) compared with sMC and HC. Smaller cerebellar volumes correlated with greater dystonia severity (BFMDRS, {rho} = -0.475, p = 0.019) while lower basal ganglia NAD ratios correlated with higher MDS-UPDRS-III ({rho} = -0.472, p=0.041) and TWSTRS scores ({rho} = -0.477, p = 0.039). Conclusions31P-MRSI and volumetric MRI reveal region- and subgroup-specific metabolic and structural alterations in GCH1 mutation carriers, linking basal ganglia vulnerability and cerebellar adaptation to clinical severity.

Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by reduced expression of the survival motor neuron (SMN) protein. In addition to affecting motor neuron survival, SMN deficiency impacts multisystem physiology and neurotransmission. Dopaminergic dysfunction has been reported in mouse models of SMA, leading to postural and locomotor impairments that improve upon treatment with L-DOPA and benserazide. However, whether altered dopamine metabolism contributes to clinical symptoms in SMA patients remains unclear. To investigate this issue, we conducted a real-world observational study involving pediatric patients with SMA1, SMA2, and SMA3. We performed a longitudinal measurement of the main dopamine-related catabolites - 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) - in cerebrospinal fluid (CSF) samples collected at baseline and after five intrathecal doses of Nusinersen, an SMN-enhancing therapy. No significant differences were observed in CSF DOPAC and HVA levels across SMA types or following treatment, and no association emerged with SMN2 copy number. In contrast, lower baseline DOPAC levels were detected in SMA1 patients requiring gastrostomy and tracheostomy, and were associated with reduced improvement on the CHOP-INTEND scale. These findings suggest that reduced central dopaminergic turnover reflects disease progression in SMA1 and is associated with more severe clinical impairment and limited functional recovery.

BackgroundDisorders affecting the spinal cord (myelopathies) can cause severe disability. Despite diagnostic advances, approximately 12-18% of myelopathy cases continue to elude an etiological diagnosis, hampering effective treatment. MethodsThis retrospective, multicenter, tertiary care cohort study conducted from 2014 to 2025 evaluated archived biofluids from patients with IM, known autoimmune myelitis, or other neurological diseases (ONDs). Proteome-wide phage display was used to discover novel autoantibodies. Targeted immunoassays were used to screen for a candidate autoantibody. Downstream metabolites were measured in the cerebrospinal fluid (CSF). ResultsAutoantibodies targeting the transcobalamin receptor (CD320) responsible for cellular transport of vitamin B12 were identified in 18 out of 32 IM patients (56%) in a discovery cohort. Bioactive B12 concentration was decreased in the CSF of anti-CD320 positive patients compared to OND controls (P = 0.0273), indicative of autoimmune B12 central deficiency (ABCD). Compared to anti-CD320 negative IM cases, anti-CD320 positive IM cases demonstrated a higher frequency of subacute time course (56% vs 7%, P = 0.008), normal CSF profile (83% vs 50%, P = 0.044), and dorsolateral spinal cord abnormalities on magnetic resonance imaging (MRI) (61% vs 7%, P = 0.003). In two independent validation cohorts comprising 94 and 25 patients with IM, anti-CD320 was detected in 43 (46%) and 12 (48%) patients, respectively. Comorbid anti-CD320 was detected in a smaller proportion of patients with other known autoimmune etiologies of myelopathy. Five anti-CD320 positive IM patients received B12 supplementation with or without concurrent immunosuppression, and four out of five clinically improved. ConclusionsABCD is associated with a substantial proportion of IM. Screening for anti-CD320 followed by metabolic confirmation of a CNS-restricted B12 deficiency may be considered in the diagnostic evaluation of myelopathy.

ATP1A3-related syndromes represent a continuously expanding clinical spectrum and present with an extraordinarily wide range of symptoms. New phenotypes continue to emerge, posing ongoing challenges for both diagnosis and development of treatments. In this context, telemedicine offers a unique opportunity to greatly expand outreach to patients. Remote, high-resolution assessments help refine phenotypic characterization and the identification of novel and intermediate phenotypes. In this study we aimed to determine completion rates and practicality of conducting motor, speech, and neuropsychological assessments entirely via virtual visits. Although the broader recruitment included several ATP1A3-related disorders, this virtual battery was specifically developed for subjects with RDP. Participants with other ATP1A3 phenotypes enrolled in the study contributed to evaluating the overall feasibility of the workflow but were not the target population for the full battery. We recruited individuals with suspected or confirmed diagnosis of ATP1A3-related disorders, along with familial controls, from three participant clinical sites. Participants completed all study procedures through scheduled telemedicine visits using their personal devices (tablets, laptops, smartphones). A total of 59 participants were enrolled, including 46 individuals with suspected or confirmed ATP1A3 variants and 13 family member controls. Among affected patients, 18 had RDP, 12 AHC (Alternating Hemiplegia of Childhood), 4 CAPOS (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, Sensorineural hearing loss), 10 were categorized as "uncertain" and 2 with "mixed" phenotype (RDP/CAPOS and RDP/AHC). The virtual assessment battery included: (i) patient history questionnaire (PHQ), (ii) structured neurological examination adapted for virtual visits, (iii) speech recording, and (iv) extensive neuropsychological assessment. Feasibility was evaluated based on completion rates for each assessment component. Remote neurological, speech and neurocognitive/psychiatric assessments were completed by most participants with ATP1A3 phenotypes, with completion rates of 78% for motor examination and 87% for speech evaluation. The observed pattern of motor and speech impairments were consistent with prior in-person evaluations, supporting the validity and feasibility for both motor and nonmotor features of remote assessment in complex genetic neurological disease.

BackgroundChronic relapsing inflammatory optic neuropathy (CRION) is a steroid-dependent form of optic neuritis with incompletely understood pathophysiology. The identification of myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) in a substantial patient subset has challenged the diagnostic and therapeutic management. The aim of this study was to investigate clinical profiles and treatment outcomes of patients with CRION, comparing MOG-IgG-positive (MOG+) and seronegative (MOG-) subgroups. MethodsPatients from six European tertiary centers fulfilling diagnostic criteria for CRION were included. All underwent cell-based autoantibody testing. Clinical outcomes (visual acuity, annualized relapse rate), laboratory and imaging findings (MRI, OCT), and treatment responses were retrospectively analyzed. ResultsSixty patients were included (median age 33 years; 70% female); 27 (45%) were MOG+. MOG+ CRION was associated with later onset, higher ARR before treatment (median [IQR] 2 [1-3] vs. 1 [1-2], p = 0.023), and a trend toward shorter inter-relapse intervals. Additional distinguishing features included higher frequencies of antinuclear antibody positivity, elevated CSF interleukin-6, and extensive optic neuritis on MRI. Relapse burden correlated with visual acuity decline and retinal thinning. In MOG+ patients, monoclonal antibody therapy reduced the ARR (n = 21; 2 [1-3] vs. 0 [0-2], p = 0.024), primarily driven by tocilizumab (n = 11; 2 [1-3] vs. 0 [0-1], p = 0.023). In MOG-patients, rituximab and azathioprine showed a trend toward ARR reduction. ConclusionCRION represents a heterogeneous syndrome encompassing distinct subgroups. MOG+ patients demonstrate higher disease activity but respond favorably to tocilizumab. Serological testing is critical for treatment stratification and preventing relapses.

BackgroundDystonia is a debilitating movement disorder that is difficult to assess when co-existing with spasticity, as is typical in cerebral palsy (CP). Querying caregivers about their childrens movements is known to increase clinical dystonia identification. However, beyond identification, determining whether dystonia is the predominant vs. accompanying movement feature in a child with CP can guide clinical decision making, particularly regarding surgical candidacy. ObjectiveTo determine whether caregivers movement descriptions differed between children with predominant dystonia, predominant spasticity with accompanying dystonia, and predominant spasticity without dystonia. MethodsIn this cross-sectional study, we used conventional content analysis to codify caregivers descriptions of triggered involuntary movements in children with CP seen in a tertiary care CP center between 4/2023 and 12/2024. Movement feature frequencies were compared across tone types using Chi-square tests with Bonferroni corrections for multiple comparisons. ResultsOf 180 children with CP (mean age 9.2, 47.8% male), caregivers of children with predominant dystonia (50/180, 27.8%) more frequently described movements triggered by negative emotions (p<0.002) and affecting their back, trunk, and whole body (p<0.04). Caregivers of children with predominant spasticity with dystonia (99/180, 55.0%) more frequently described movements affecting a single limb (p<0.04). Caregivers of children without dystonia (31/180, 17.2%) described movements as being slight or small (p<0.008). These differences persisted even for caregivers unaware their child had dystonia (77/149, 51.6%). ConclusionsCaregivers movement descriptions differ between children with different combinations of dystonia and spasticity, which may help inform clinical management and guide communication with families about dystonia.

BackgroundMultiple sclerosis (MS) is a chronic neurodegenerative disease charac-terised by progressive neurological disability and heterogeneous symptom trajectories. Cur-rent clinical monitoring methods, including magnetic resonance imaging (MRI) and episodic neurological assessments, provide limited insight into subtle disease progression and real-world functional changes. Digital health technologies integrating multimodal biosignals and behavioural assessments may enable continuous monitoring and personalised rehabilitation for patients with MS. ObjectiveThis study aims to evaluate the clinical utility of the BodyMirror Clinical MS platform, a multimodal software-as-a-medical-device (SaMD) that combines wearable biosensors, neuroscience-based games, and machine learning algorithms to remotely monitor disease progression and deliver personalised neurorehabilitation for individuals with multiple sclerosis. MethodsThis study is a prospective, randomised, double-blind, controlled, multisite clinical trial enrolling 400 participants, including 300 individuals with multiple sclerosis and 100 healthy controls. MS participants will be randomly assigned (1:1) to either an adaptive neurorehabilitation intervention group or a control group receiving non-therapeutic digital activities matched for engagement and exposure. Participants will perform three 30-minute sessions per week over a 24-month period using the BodyMirror platform. The system integrates multiple biosignals, including electroencephalography (EEG), electromyography (EMG), inertial measurement unit (IMU) motion data, speech analysis, and behavioural performance metrics, to generate digital biomarkers of neurological function. The primary endpoint is change in Expanded Disability Status Scale (EDSS) score from baseline to 24 months. Secondary outcomes include changes in Multiple Sclerosis Functional Composite (MSFC), MRI brain volume, cognitive performance, patient-reported outcomes, adherence to digital rehabilitation, and health-economic outcomes. ConclusionsThis trial will provide the first large-scale clinical evaluation of a mul-timodal digital neurotechnology platform combining wearable biosensors and game-based neurorehabilitation for remote management of multiple sclerosis. If successful, BodyMirror Clinical MS may enable scalable remote monitoring, earlier detection of disease progres-sion, and personalised digital rehabilitation for individuals living with MS.

Dystonia treatment evaluation in cerebral palsy (CP) is limited by the lack of clinician-assessed scales linking dystonia severity to functional impact. We asked 7 pediatric movement disorder specialists to review videos of 27 children with CP while performing an upper extremity task and while walking. Experts rated arm and leg dystonia severity using the Global Dystonia Severity Rating Scale (GDRS) and task-specific functional impact on a five-point scale adapted from the Dyskinetic Cerebral Palsy Functional Impact Scale. Arm GDRS scores correlated with functional impact on the upper extremity task (linear regression R^2=0.48, p=0.0005). Leg GDRS scores correlated with gait impact (R^2=0.43, p=0.001). A four-point increase in total GDRS corresponded to a one-point worsening in combined functional impact. By demonstrating how expert-rated limb dystonia severity correlates with task-specific functional impact in children with CP, these results could help clinically identify functionally-meaningful differences in dystonia severity.

BackgroundAlthough neurogenic orthostatic hypotension (nOH) is a common and debilitating feature of multiple system atrophy (MSA), little is known about the burden of symptoms in the real world. ObjectivesTo design and conduct a cross-sectional community-based research survey targeting patients with MSA, with and without nOH. MethodsWe recruited patients with MSA to complete an anonymous online survey covering three core themes: 1) timely diagnosis, 2) nOH pharmacotherapy and refractory symptoms, and 3) confidence in physician knowledge. Responses were grouped by pre-specified diagnostic certainty levels. Relationships between symptoms, function, and pharmacotherapy were assessed using univariate and multivariate methods. ResultsWe analyzed 259 respondents with a self-reported diagnosis of MSA (age: M=64.38, SD=8.09 years; 44% female). In total, 42% also had a diagnosis nOH; 40% had symptoms highly suspicious of nOH, but no diagnosis; and 21% reported having never had their blood pressure measured in the standing position at a clinical visit. Treatment with a pressor agent was independently associated with the presence of other symptoms of autonomic failure. Each additional nOH symptom reported increased the odds of requiring pharmacotherapy by 18%. Yet, despite anti-hypotensive medication use, 97% of patients reported limitations in their ability to bathe, cook, or arise from a chair/bed with 76% needing caregiver support for refractory nOH symptoms. ConclusionsThis cross-sectional representative sample shows nOH is underrecognized and undertreated in MSA patients, leading to substantial functional limitations. It is our hope that these findings are leveraged for planning future trials and advocating for better treatments.

IntroductionThe 2024 McDonald criteria incorporate the central vein sign (CVS) and paramagnetic rim lesions (PRL) as supportive imaging biomarkers for MS diagnosis. While susceptibility-weighted-imaging (SWI) and T2*-weighted echo-planar-imaging (EPI) are generally used to assess CVS/PRL, their relative performance remains unclear. This study compared high-resolution isotropic-T2*-EPI with non-isotropic SWI for CVS/PRL detection. Materials and MethodsIn this multi-centre study, 21 patients with MS underwent harmonized 3T-MRI including EPI and SWI. CVS and PRL were evaluated according to NAIMS criteria. Whole-brain and controlled lesion analyses on 120 pre-selected lesions were performed independently for each contrast, with EPI serving as reference standard. ResultsIn whole-brain analyses, SWI showed good sensitivity for CVS eligibility and positivity (AC1=0.68-0.78) but significant directional disagreement with EPI (p<0.0001). Discrepancies were primarily attributed to limited lesion-parenchyma contrast and venous visibility on SWI, which improved using low-flip-angle SWI. Controlled lesion analyses supported these observations. For PRL, SWI demonstrated high sensitivity (88%) and precision (97%) compared to EPI, though systematic bias persisted (p<0.001). Controlled lesion analyses showed more balanced, albeit moderate performance. ConclusionSWI diverged systematically from EPI for CVS and PRL detection. When available, EPI should be preferred, while optimised low-flip-angle SWI may serve as an alternative to conventional SWI.

BackgroundPleuroparenchymal fibroelastosis (PPFE) is a rare, fibrotic lung disease with poor prognosis, usually affecting adults which most commonly occurs idiopathically. Biallelic pathogenic variants in DGUOK cause mitochondrial DNA (mtDNA) depletion syndrome, predominantly affecting infants with severe hepatic and neurological symptoms. Detailed description of pulmonary manifestations with late-onset presentation have not been reported. MethodsWe describe nine patients with PPFE and DGUOK-associated mitochondriopathy. Clinical, radiological, histopathological, and genetic data were systematically collected from all patients. Functional studies, single nucleus RNA sequencing (snRNAseq), immunofluorescence staining, transmission electron microscopy and respiratory chain enzyme activity assays were conducted on patient-derived fibroblasts, muscle or lung tissues. mtDNA content quantification was performed on whole genome sequencing (WGS) data. ResultsAll patients (ages 5-36) presented with progressive dyspnea, weight loss and some with spontaneous pneumothoraces. Chest computed tomography and lung biopsies showed features of PPFE. Biallelic pathogenic DGUOK variants were identified in all patients, seven of them carry an unreported intronic variant leading to mtDNA depletion. snRNAseq of lung tissue from four pediatric patients identified Aberrant Basaloid cells and intermediate cells as their precursor localized at the fibrotic edge. Mitochondrial alterations were identified by electron microscopy. ConclusionPPFE in children and young adults is associated with DGUOK-related mitochondriopathy. For the first time, we demonstrate Aberrant Basaloid cells in pediatric fibrotic lung tissue. Since pulmonary involvement may be underrecognized or misinterpreted and the clinical presentation may not always be typical of a mitochondriopathy, we recommend genetic testing in all patients with PPFE of unknown origin.

Importance: NGLY1 (N-Glycanase 1) Deficiency is an ultra-rare autosomal recessive disorder affecting ~165 patients worldwide, characterized by developmental delay, hyperkinetic movement disorders, and shortened life expectancy. Despite its severe neurological manifestations, comprehensive neuroimaging characterization has been limited to case reports and small descriptive studies. Objective: To investigate alterations in brain morphology in patients with NGLY1 Deficiency and determine whether these metrics associate with clinical phenotypes. Design, Setting, and Participants: This case series analyzed real-world MRI scans performed on 11 patients with NGLY1 Deficiency between 1999-2023 at sites across the globe. Ages ranged from 2 to 19 years at scan time (5 female, 6 male). Exposure: Molecular diagnosis of NGLY1 Deficiency. Main Outcomes and Measures: Cortical and subcortical morphology, including subcortical volume, and cortical thickness, surface area, volume, and curvature, were measured with 3-dimensional T1-weighted magnetic resonance imaging (MRI) scans. Z-scores were calculated using normative models from CentileBrain for patients >3 years old or custom models for patients <3 years old. Clinical phenotypes were matched to Human Phenotype Ontology codes. Results: 16 scans from 11 patients met quality criteria for analysis. Both age groups (under and over 3 years old) showed significantly reduced subcortical volumes, particularly in bilateral thalamus and putamen. Younger patients demonstrated widespread reductions in cortical surface area, volume, and curvature, indicating altered gyrification patterns. Older patients showed thinner dorsal and thicker ventral cortical regions with limited surface area reductions. Thalamic volume reduction in older patients correlated with gait disturbance, dysphagia, and EEG abnormalities, with additional cortical associations with sleep and hearing abnormalities. Seizure presence in younger patients correlated with altered cortical thickness, surface area, and curvature patterns. Conclusions and Relevance: NGLY1 Deficiency is associated with pervasive alterations in brain development affecting both subcortical and cortical morphology. Age-dependent patterns of cortical alterations indicate disrupted neurodevelopmental trajectories that may reflect impaired neuronal migration and/or altered synaptic pruning. Correlations with clinical variables suggest that these measures may serve as useful biomarkers for tracking disease progression and/or treatment efficacy. These findings provide a comprehensive neuroimaging characterization of NGLY1 Deficiency and establish a foundation for understanding brain structure-function relationships in this ultra-rare disorder.

Study ObjectivesAutomated sleep staging underpins clinical sleep assessment and translational neuroscience, yet most data analyses work addresses human and animal data separately. We tested whether a seizure-oriented machine learning framework can be repurposed for three-state sleep staging in humans and rats, and whether models trained solely on rodent data can be applied directly to human recordings using an explicit cross-species montage. MethodsWe used the PySeizure, a standardised EEG preprocessing and seizure-detection framework, together with TinySleepNet as the core classifier. Models were trained and evaluated on the Sleep-EDF expanded Sleep Cassette subset (three classes: wake, non-rapid eye movement sleep, rapid eye movement sleep), then applied without fine-tuning to the Sleep Telemetry subset. The same pipeline was used on a SYNGAP1 rat dataset with analogous three-state labels. A novel human-rat electroencephalography montage mapped rat electrodes to putative human scalp homologues, enabling direct application of rat-trained models to Sleep Cassette. ResultsWithin Sleep Cassette, the accuracy in three-stage sleep classification was 0.95. Applying this model directly to Sleep Telemetry yielded an accuracy of 0.89. On the rodent dataset, accuracy was 0.78. When the rat-trained model was applied directly to Sleep Cassette, accuracy was 0.68. ConclusionsA single deep learning pipeline can support robust three-state sleep staging in humans and rodents and retains meaningful performance under both human cross-subset and rat-to-human transfer without any retraining or fine-tuning. The rat-trained models above-chance performance on human data, achieved without human training samples, shows that rodent-derived representations can contribute directly to human sleep staging when constrained by an anatomically informed montage, linking preclinical rodent recordings and clinical human sleep studies.

Critically ill children admitted to pediatric intensive care units (PICUs) face significant neurological risks, but it remains unclear whether neurological assessments are adequately integrated into clinical routines. We aimed to evaluate the global scientific landscape regarding neurological examination in PICU, combining bibliometric analysis with clinical-guided critical analysis. A comprehensive search was conducted on the Web of Science Core Collection (WoS-CC) using terms related to pediatric critical care and neurological evaluation. Eligible publications were original research articles approaching neurological assessment during PICU stay. Bibliometric indicators, science mapping, and study design profiling were analyzed. In a separate, clinically guided interpretative layer, reporting patterns related to timing, tools, and strategies of neurological assessment were synthesized. From 359 records, 128 articles met inclusion criteria. The United States accounted for over half of the publications, while most studies employed retrospective designs and focused on traumatic brain injury or cardiac arrest. Despite the relevance of clinical neurological examination - especially using the Glasgow Coma Scale (GCS) and Pediatric Cerebral Performance Category (PCPC), advanced neuromonitoring tools, e.g., EEG, intracranial pressure monitoring, and biomarkers were inconsistently applied. Notably, neurological evaluations were often underreported at admission and discharge and rarely extended to non-neurological PICU conditions. Our findings reveal a critical gap between the neurological vulnerability of PICU patients, and the limited, inconsistent assessment strategies reported in the literature. Expanding structured neurological evaluation to all critically ill children, not only those with overt neurological diagnoses, seems essential to promote brain health and long-term recovery.

IRF2BPL-related disorder is a neurodevelopmental disorder caused by heterozygous variants in the IRF2BPL (Interferon Regulatory Factor 2 Binding Protein-Like) gene. The few reports available in the literature suggest that common symptoms include developmental delay, intellectual disability and developmental regression. There are no reports of genotype-phenotype correlations. We developed a retrospective and prospective patient-reported survey to assess diagnostic information, presenting symptoms and longitudinal follow-up of neurological symptoms for up to two years. Clinical information was available for all 32 participants and was highly variable in regards to age at symptom onset, severity of neurologic manifestations, and progressivity. For 27 of the 32 participants, diagnostic genetic test results were available. Genetic mutation analysis revealed 22 individuals with truncating variants and five participants with unique missense variants in IRF2BPL. The study data support the hypothesis that IRF2BPL missense variants are associated with a less severe disease presentation and progression than participants with truncating variants. The purpose of this study is to further define IRF2BPL-related disorder and provide more clinical and molecular insight into this ultra-rare disease. Highlights- Patient-reported clinical history at diagnosis and up to two years of follow up - The clinical spectrum is increasingly heterogeneous - We report 32 patients, 27 with noted IRF2BPL variants, 14 being novel to literature. - Data supports the notion that IRF2BPL missense variants may be associated with less severe disease than truncations (nonsense/frameshifts).

Nusinersen was the first disease modifying treatment approved for 5q spinal muscular atrophy (SMA). Long-term results of broad populations, particularly for adolescents and adults, remain limited. We conducted a population-based, ambispective observational study of all SMA patients living in the Valencian Community (Spain) between September 2017 and December 2022 and follow-up until December 2025. Demographic, clinical and motor outcomes using revised SMA Functional Composite Score (SMA-FCR) were collected. Patients were classified as responders or non-responders. The risk for nusinersen discontinuation was assessed with a Bayesian model, and SMA-FCR trajectories with mixed linear regression. Of 72 patients included, 18 were <12 years old (all treated with nusinersen) and 54 were [&ge;]12 years (28 treated; 26 untreated) at the baseline visit. After a median of 7 years, all patients <12 years were classified as responders versus 68% of patients [&ge;]12 years. Discontinuation rates were 11% in children compared to75% in the older cohort. In patients [&ge;]12 years, reasons for discontinuation included: treatment burden (71%), and loss(53%) or lack of benefit (43 %). Lower baseline SMA-FCR (expEstimate= 0.84 [0.718,0.93], prob:1) and older age (expEstimate=1.028 [1.011,1.055], prob:1) independently predicted higher discontinuation risk. Sustained nusinersen treatment was independently associated with SMA-FCR increase, while untreated and discontinued patients showed slight deterioration over time. In this long-term population-based study, nusinersen use and persistence was high in children but declined significantly after age 12 due to treatment burden and limited efficacy. However, a proportion of adolescents and adults (those younger and with higher baseline function) experienced sustained benefit.

BackgroundPeri-synaptic astrocyte processes (PAPs) play a fundamental role in synapse formation and function. Central afferent synapse loss and astrocyte dysfunction greatly impede sensory-motor circuitry in spinal muscular atrophy (SMA) disease progression, however mechanisms underpinning tripartite synapse dysfunction remains to be fully elucidated. The aims of this study were to further define PAP and motor neuron synaptic defects in human SMA disease pathology and implement a therapeutic intervention strategy to improve motor neuron function. MethodsWe derived astrocyte monocultures and motor neuron astrocyte co-cultures from healthy and SMA patient induced pluripotent stem cell (iPSC) lines to assess intrinsic astrocyte filopodia defects and phenotypes occurring at the synapse-PAP interface, respectively, using cell surface capture mass spectrometry proteomics, confocal and super resolution microscopy, synaptogliosome isolation, and electrophysiology. ResultsSMA astrocytes demonstrated intrinsic filopodia actin defects featuring low abundance of actin-associated cell surface N-glycoproteins, and decreased filopodia density and CDC42-GTP levels after actin remodeling stimulation. This phenotype is likely driven by the significant reduction of CD44 and phosphorylated ezrin, radixin and moesin ERM proteins (pERM) within SMA astrocyte filopodia. The dual combination of SMN1 gene therapy and forskolin treatment, an adenylyl cyclase activator leading to increased cyclic adenosine monophosphate (cAMP) levels and actin signaling pathway stimulation, led to extensive branching and increased filopodia density of SMA astrocytes during actin remodeling. SMA patient-derived motor neuron and astrocyte co-cultures, particularly samples derived from male patient iPSC lines, demonstrated a significant decrease in synapse number, actin-associated pre-synaptic neurotransmitter release protein, synapsin I (SYN1), and PAP-associated expression of pERM and glutamate transporter, EAAT1. Our astrocyte-targeted SMN1 augmentation and forskolin treatment paradigm restored SYN1 protein levels within the SMA synaptogliosome, resulting in significant increases in motor neuron synapse formation and function, but did not fully restore PAP-associated proteins levels at the synapse. ConclusionsSMA astrocytes demonstrate intrinsic actin-associated defects within filopodia, which correlates with decreased pERM levels at tripartite motor neuron synapses. We also define a SMN- and cAMP-targeted treatment paradigm that significantly increases pre-synaptic neurotransmitter release protein levels to improved SMA motor neuron synapse formation and function. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=117 SRC="FIGDIR/small/714618v1_ufig1.gif" ALT="Figure 1"> View larger version (44K): org.highwire.dtl.DTLVardef@1257ab8org.highwire.dtl.DTLVardef@19c0010org.highwire.dtl.DTLVardef@c84552org.highwire.dtl.DTLVardef@3f1e62_HPS_FORMAT_FIGEXP M_FIG C_FIG