Children with hemiplegic cerebral palsy exhibit diverse sensory deficits linked to varied atypical brain reorganization patterns. The underlying mechanisms of these patterns remain poorly understood. Using multimodal neuroimaging, we associate functional and structural neuroplasticity in the somatosensory system of children with hemiplegic cerebral palsy with lesion type and behavioural outcome. We hypothesize that different lesion types produce distinct patterns of neuroplasticity, which correlate with varying levels of sensory and motor behavioural deficits. We examined 22 children with hemiplegic cerebral palsy (7 with cortical-subcortical, 12 with periventricular, and 3 with other lesions) and 24 age-matched neurotypical controls. We assessed the somatosensory outcomes through touch sensitivity and two-point discrimination measures, and motor outcomes through movement range, accuracy, dexterity, and fluency measures. We quantified the integrity of ascending sensory and somatosensory commissural fibres with diffusion-weighted MRI and measured cortical responses to haptic stimulation with magnetoencephalography and high-density EEG. Children with cortical-subcortical lesions demonstrated higher sensory thresholds and worse movement quality in the paretic hand compared to the periventricular lesion (P < 0.05) and control group (P < 0.01). Functional imaging revealed suppressed primary and secondary somatosensory cortical activations (P < 0.01) and prolonged primary somatosensory cortex latency (P < 0.05) in the more affected hemisphere in response to paretic hand stimulation. These children also exhibited more pronounced disruption of interhemispheric functional balance (P < 0.05). Tractography showed greater microstructural damage-increased mean (P < 0.01), axial (P < 0.01), and radial (P < 0.01) diffusivities-in both ascending sensory and commissural fibres in the more affected hemisphere of the cortical-subcortical lesion group. In contrast, the periventricular lesion group showed unilateral damage to ascending sensory fibres (P < 0.01) and bilateral damage to commissural fibres (P < 0.05). More severe diffusion abnormalities were associated with lower cortical amplitudes (Rho = -0.58 to -0.78, P < 0.05), delayed latencies (Rho = 0.69, P < 0.05), and decreased lateralization (Rho = -0.62 to -0.72, P < 0.05). Moderate to strong correlations were observed between cortical amplitudes and touch sensitivity (Rho = -0.56 to -0.60, P < 0.05) and discriminability (Rho = -0.77, P < 0.01). Our findings show that children with hemiplegic cerebral palsy exhibit distinct structural and functional neuroplasticity patterns based on lesion type. Cortical-subcortical lesions lead to more extensive somatosensory damage, while periventricular lesions are linked to greater neuroplastic potential. These insights deepen our understanding of neuroplasticity mechanisms and highlight targets for optimizing therapeutic interventions.

Sense of touch is essential for our interactions with external objects and fine control of hand actions. Despite extensive research on human somatosensory processing, it is still elusive how involved brain regions interact as a dynamic network in processing tactile information. Few studies probed temporal dynamics of somatosensory information flow and reported inconsistent results. Here, we examined cortical somatosensory processing through magnetic source imaging and cortico-cortical coupling dynamics. We recorded magnetoencephalography signals from typically developing children during unilateral pneumatic stimulation. Neural activities underlying somatosensory evoked fields were mapped with dynamic statistical parametric mapping, assessed with spatiotemporal activation analysis, and modeled by Granger causality. Unilateral pneumatic stimulation evoked prominent and consistent activations in the contralateral primary and secondary somatosensory areas but weaker and less consistent activations in the ipsilateral primary and secondary somatosensory areas. Activations in the contralateral primary motor cortex and supramarginal gyrus were also consistently observed. Spatiotemporal activation and Granger causality analysis revealed initial serial information flow from contralateral primary to supramarginal gyrus, contralateral primary motor cortex, and contralateral secondary and later dynamic and parallel information flows between the consistently activated contralateral cortical areas. Our study reveals the spatiotemporal dynamics of cortical somatosensory processing in the normal developing brain.

Duchenne muscular dystrophy is a genetically based neuromuscular disorder characterized by progressive physical impairment and cardiomyopathy in children, leading to fatal cardiac or respiratory failure. Duchenne muscular dystrophy shares some overlapping clinical features with other disorders, complicating clinical differentiation. We hypothesized that some Duchenne muscular dystrophy patients may have a secondary neuromuscular disorders that could negatively skew data during pharmaceutical clinical trials and lead to incomplete treatment plans. Consecutive genetic panels on 353 patients were reviewed. Thirty-two (32; 9.1%) patients with Duchenne muscular dystrophy were identified. Three (3; 9.4%) were found to have at least 1 genetically confirmed secondary neuromuscular disorder. Overlooking these coexisting disorders could lead to unexpected treatment failures, potentially affecting medication efficacy in trials or commercial use. Secondary neuromuscular disorders should be considered in Duchenne muscular dystrophy patients before clinical trial enrollment or treatment planning, with expanded genetic testing, such as whole exome sequencing or whole genome sequencing, likely to reveal even more secondary disorders.

BackgroundDeep brain stimulation (DBS) has been increasingly used in the management of dyskinetic cerebral palsy (DCP). Data on long-term effects and the safety profile are rare. ObjectivesWe assessed the efficacy and safety of pallidal DBS in pediatric patients with DCP. MethodsThe STIM-CP trial was a prospective, single-arm, multicenter study in which patients from the parental trial agreed to be followed-up for up to 36 months. Assessments included motor and non-motor domains. ResultsOf the 16 patients included initially, 14 (mean inclusion age 14 years) were assessed. There was a significant change in the (blinded) ratings of the total Dyskinesia Impairment Scale at 36 months. Twelve serious adverse events (possibly) related to treatment were documented. ConclusionDBS significantly improved dyskinesia, but other outcome parameters did not change significantly. Investigations of larger homogeneous cohorts are needed to further ascertain the impact of DBS and guide treatment decisions in DCP. & COPY; 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Abstract Dystrophinopathies result from mutations to the DMD gene. We report 5 boys in 3 families with heterogenous phenotypes due to a point mutation in the DMD gene: a hemizygous tyrosine-to-cysteine change in exon 15 (c.1724T>C) resulting in an amino acid substitution of leucine to proline at codon 575. This mutation has been reported before, with at least 3 prior patients presenting with similar clinical findings of myalgia, myoglobinuria, and occasional muscle cramping. The mutation on DMD c.1724T>C (p.Leu575Pro) is listed in the Clinvar database as a variant of unknown significance. Our report provides contributing evidence that this alteration should be classified as pathogenic.

Background Most reported patients carrying GNAO1 mutations showed a severe phenotype characterized by early-onset epileptic encephalopathy and/or chorea. Objective The aim was to characterize the clinical and genetic features of patients with mild GNAO1-related phenotype with prominent movement disorders. Methods We included patients diagnosed with GNAO1-related movement disorders of delayed onset (>2 years). Patients experiencing either severe or profound intellectual disability or early-onset epileptic encephalopathy were excluded. Results Twenty-four patients and 1 asymptomatic subject were included. All patients showed dystonia as prominent movement disorder. Dystonia was focal in 1, segmental in 6, multifocal in 4, and generalized in 13. Six patients showed adolescence or adulthood-onset dystonia. Seven patients presented with parkinsonism and 3 with myoclonus. Dysarthria was observed in 19 patients. Mild and moderate ID were present in 10 and 2 patients, respectively. Conclusion We highlighted a mild GNAO1-related phenotype, including adolescent-onset dystonia, broadening the clinical spectrum of this condition. (c) 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

Background: Edasalonexent (CAT-1004) is an orally-administered novel small molecule drug designed to inhibit NF-κB and potentially reduce inflammation and fibrosis to improve muscle function and thereby slow disease progression and muscle decline in Duchenne muscular dystrophy (DMD). Objective: This international, randomized 2 : 1, placebo-controlled, phase 3 study in patients ≥4 – < 8 years old with DMD due to any dystrophin mutation examined the effect of edasalonexent (100 mg/kg/day) compared to placebo over 52 weeks. Methods: Endpoints were changes in the North Star Ambulatory Assessment (NSAA; primary) and timed function tests (TFTs; secondary). Assessment of health-related function used the Pediatric Outcomes Data Collection tool (PODCI). Results: One hundred thirty one patients received edasalonexent (n = 88) and placebo (n = 43). At week 52, differences between edasalonexent and placebo for NSAA total score and TFTs were not statistically significant, although there were consistently less functional declines in the edasalonexent group. A pre-specified analysis by age demonstrated that younger patients (≤6.0 years) showed more robust and statistically significant differences between edasalonexent and placebo for some assessments. Treatment was well-tolerated and the majority of adverse events were mild, and most commonly involved the gastrointestinal system (primarily diarrhea). Conclusions: Edasalonexent was generally well-tolerated with a manageable safety profile at the dose of 100 mg/kg/day. Although edasalonexent did not achieve statistical significance for improvement in primary and secondary functional endpoints for assessment of DMD, subgroup analysis suggested that edasalonexent may slow disease progression if initiated before 6 years of age. (NCT03703882)

Children with hemiplegic cerebral palsy (HCP) often show disturbances of somatosensation. Despite extensive evidence of somatosensory deficits, neurophysiological alterations associated with somatosensory deficits in children with HCP have not been elucidated. Here, we aim to assess phase synchrony within and between contralateral primary (S1) and secondary (S2) somatosensory areas in children with HCP. Intra-regional and inter-regional phase synchronizations within and between S1 and S2 were estimated from somatosensory evoked fields (SEFs) in response to passive pneumatic stimulation of contralateral upper extremities and recorded with pediatric magnetoencephalography (MEG) in children with HCP and typically developing (TD) children. We found aberrant phase synchronizations within S1 and between S1 and S2 in both hemispheres in children with HCP. Specifically, the less-affected (LA) hemisphere demonstrated diminished phase synchronizations after the stimulus onset up to -120 ms compared to the more-affected (MA) hemisphere and the dominant hemisphere of TD children, while the MA hemisphere showed enhanced phase synchronizations after -100 ms compared to the LA hemisphere and the TD dominant hemisphere. Our findings indicate abnormal somatosensory functional connectivity in both hemispheres of children with HCP.

Spermatogenesis-associated 5 like 1 (SPATA5L1) represents an orphan gene encoding a protein of unknown function. We report 28 bi-allelic variants in SPATA5L1 associated with sensorineural hearing loss in 47 individuals from 28 (26 unrelated) families. In addition, 25/47 affected individuals (53%) presented with microcephaly, developmental delay/intellectual disability, cerebral palsy, and/or epilepsy. Modeling indicated damaging effect of variants on the protein, largely via destabilizing effects on protein domains. Brain imaging revealed diminished cerebral volume, thin corpus callosum, and periventricular leukomalacia, and quantitative volumetry demonstrated significantly diminished white matter volumes in several individuals. Immunofluorescent imaging in rat hippocampal neurons revealed localization of Spata5l1 in neuronal and glial cell nuclei and more prominent expression in neurons. In the rodent inner ear, Spata5l1 is expressed in the neurosensory hair cells and inner ear supporting cells. Transcriptomic analysis performed with fibroblasts from affected individuals was able to distinguish affected from controls by principal components. Analysis of differentially expressed genes and networks suggested a role for SPATA5L1 in cell surface adhesion receptor function, intracellular focal adhesions, and DNA replication and mitosis. Collectively, our results indicate that bi-allelic SPATA5L1 variants lead to a human disease characterized by sensorineural hearing loss (SNHL) with or without a nonprogressive mixed neurodevelopmental phenotype.

Purpose of Review This review will provide an update on the current status of deep brain stimulation in pediatric onset dystonias. Recent Findings Dystonia is a complex movement disorder that may occur in isolation or in combination with other abnormalities of tone and posture. The dystonias represent a heterogeneous group of movement disorders that can be progressive, painful, and severely disabling. Genetic and extrinsic factors may influence the treatment response. Pharmacologic treatment often has limited effectiveness and unacceptable, unwanted effects. Neuromodulation by deep brain stimulation (DBS) is a targeted therapy that continues to evolve as a treatment option for children with medically refractory dystonia due to a variety of etiologies. We share some insights from our surgical experience with 124 children with dystonia treated by DBS and review the current literature on the use of DBS in pediatric onset dystonia. Summary Advances in surgical options make the surgery more tolerable for young children. Secondary dystonia, in particular cerebral palsy, is more common than primary genetic etiologies. Both may respond to DBS, which may be considered once medical management has failed. Data sharing through registry platforms such as PEDiDBS is a vital component for expanding our knowledge base.

The endosomal sorting complexes required for transport (ESCRTs) are essential for multiple membrane modeling and membrane-independent cellular processes. Here we describe six unrelated individuals with de novo missense variants affecting the ATPase domain of VPS4A, a critical enzyme regulating ESCRT function. Probands had structural brain abnormalities, severe neurodevelopmental delay, cataracts, growth impairment, and anemia. In cultured cells, overexpression of VPS4A mutants caused enlarged endosomal vacuoles resembling those induced by expression of known dominant-negative ATPase-defective forms of VPS4A. Proband-derived fibroblasts had enlarged endosomal structures with abnormal accumulation of the ESCRT protein IST1 on the limiting membrane. VPS4A function was also required for normal endosomal morphology and IST1 localization in iPSC-derived human neurons. Mutations affected other ESCRT-dependent cellular processes, including regulation of centrosome number, primary cilium morphology, nuclear membrane morphology, chromosome segregation, mitotic spindle formation, and cell cycle progression. We thus characterize a distinct multisystem disorder caused by mutations affecting VPS4A and demonstrate that its normal function is required for multiple human developmental and cellular processes.

Background: Interactive neuromodulation represents the evolving frontier in surgical treatment of a variety of disorders involving the sensory organs and nervous system. Building on the advances of pioneering neurologists and neurosurgeons, progress has been made since the introduction of deep brain stimulation (DBS). Microelectrode recording has greatly aided our understanding of the underlying pathogenesis of movement disorders and the effects of electrical stimulation. The introduction of image - guided systems to provide targeted, controlled neuro-stimulation to specific brain areas is an emerging technique for implantation and may have special appeal for pediatric patients.Rationale/Aim: DBS is generally accepted as a treatment for some forms of childhood dystonia. Its potential role in other pediatric movement disorders is less well established. This is important, as most forms of dystonia begin in childhood or adolescence and many are inadequately responsive to current pharmacotherapy and other interventions. Nonetheless, many aspects of deep brain stimulation need clarification.Conclusion: This can only be accomplished through an organized platform for data sharing that will allow questions to be asked and hopefully answered, with the ultimate goal of developing evidence based practice based guidelines elucidating the role of DBS in pediatric patients. (C) 2016 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.

Movement disorders in children are causally and clinically heterogeneous and present in a challenging developmental context. Treatment options are broad ranging, from pharmacotherapy to invasive neuromodulation and experimental gene and stem cell therapies. The clinical effects of these therapies are variable and often poorly sustained, and only a few of the management strategies used in paediatric populations have been tested in randomised controlled studies with age-appropriate cohorts. Identification of the most appropriate treatment is uniquely challenging in children because of the incomplete knowledge about the pathophysiology of movement disorders and their influence on normal motor development; thus, effective therapeutic options for these children remain an unmet need. It is vital to transfer the expanding knowledge of the movement disorders into the development of novel symptomatic or, ideally, disease-modifying treatments, and to assess these therapeutic strategies in appropriately designed and well done trials.

Whole-exome sequencing (WES) represents a significant breakthrough in clinical genetics, and identifies a genetic etiology in up to 30% of cases of intellectual disability (ID). Using WES, we identified seven unrelated patients with a similar clinical phenotype of severe intellectual disability or neurodevelopmental delay who were all heterozygous for de novo truncating variants in the AT-hook DNA-binding motif-containing protein 1 (AHDC1). The patients were all minimally verbal or nonverbal and had variable neurological problems including spastic quadriplegia, ataxia, nystagmus, seizures, autism, and self-injurious behaviors. Additional common clinical features include dysmorphic facial features and feeding difficulties associated with failure to thrive and short stature. The AHDC1 gene has only one coding exon, and the protein contains conserved regions including AT-hook motifs and a PDZ binding domain. We postulate that all seven variants detected in these patients result in a truncated protein missing critical functional domains, disrupting interactions with other proteins important for brain development. Our study demonstrates that truncating variants in AHDC1 are associated with ID and are primarily associated with a neurodevelopmental phenotype.

The authors compared the outcomes of 17 children aged 7 to 15 years with DYT1 dystonia or cerebral palsy following deep brain stimulation. While patients with cerebral palsy presented with significantly greater motor disability than the DYT1 cohort at baseline, both groups demonstrated improvement at 1 year (cerebral palsy = 24%; DYT1 = 6%). The group as a whole demonstrated significant improvement on the Barry-Albright Dystonia Scale across time. Gains in motor function were apparent in both axial and appendicular distributions involving both upper and lower extremities. Gains achieved by 6 months were sustained in the cerebral palsy group, whereas the DYT1 group demonstrated continued improvement with ongoing pallidal stimulation beyond 18 months. Young patients with dystonia due to cerebral palsy responded comparably to patients with DYT1 dystonia. The severity of motor impairment in patients with cerebral palsy at baseline and follow-up raises the issue of even earlier intervention with neuromodulation in this population to limit long-term motor impairments due to dystonia.

Secondary dystonia encompasses a heterogeneous group with different etiologies. Cerebral palsy is the most common cause. Pharmacological treatment is often unsatisfactory. There are only limited data on the therapeutic outcomes of deep brain stimulation in dyskinetic cerebral palsy. The published literature regarding deep brain stimulation and secondary dystonia was reviewed in a meta-analysis to reevaluate the effect on cerebral palsy. The Burke-Fahn-Marsden Dystonia Rating Scale movement score was chosen as the primary outcome measure. Outcome over time was evaluated and summarized by mixed-model repeated-measures analysis, paired Student t test, and Pearson's correlation coefficient. Twenty articles comprising 68 patients with cerebral palsy undergoing deep brain stimulation assessed by the Burke-Fahn-Marsden Dystonia Rating Scale were identified. Most articles were case reports reflecting great variability in the score and duration of follow-up. The mean Burke-Fahn-Marsden Dystonia Rating Scale movement score was 64.94 ± 25.40 preoperatively and dropped to 50.5 ± 26.77 postoperatively, with a mean improvement of 23.6% (P < .001) at a median follow-up of 12 months. The mean Burke-Fahn-Marsden Dystonia Rating Scale disability score was 18.54 ± 6.15 preoperatively and 16.83 ± 6.42 postoperatively, with a mean improvement of 9.2% (P < .001). There was a significant negative correlation between severity of dystonia and clinical outcome (P < .05). Deep brain stimulation can be an effective treatment option for dyskinetic cerebral palsy. In view of the heterogeneous data, a prospective study with a large cohort of patients in a standardized setting with a multidisciplinary approach would be helpful in further evaluating the role of deep brain stimulation in cerebral palsy. © 2013 Movement Disorder Society.

OBJECTIVE: To compare 6 and 12 month outcomes with pallidal DBS treatment in children with Dyt-1 dystonia and cerebral palsy.